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Damien Ajavon is a contemporary and conceptual textile artist currently living and working in Montreal who describes himself as a creative mind, TV-nerd and Dollarstore-Queen. For a long time, he did not consider himself an artist because he could not draw – a skill, he believed, a good artist should have. Now, he knows better: Creativity and the ability to share visions and expressions are his paper and pen.
In Franz Hohlers Tschipo (1978), dem ersten Teil einer Trilogie, erlebt ein Schweizer Junge Abenteuer auf seltsamen Inseln. Und in Maggie Stiefvaters Serien The Raven Cycle (2012 – 2016) und The Dreamer Trilogy (2019 – ) bekämpft ein amerikanischer junger Erwachsener mit Namen Ronan Lynch magische Gefahren. Was haben Tschipo und Ronan gemeinsam? Eine seltsame Gabe: Von ihren Träumen bleibt am Morgen etwas zurück...
Dopaminerge Neurone sind vor allem im Mittelhirn lokalisiert und modulieren die Funktion der Basalganglien, welche eine wichtige Rolle bei motorischem, kognitivem und emotionalem Verhalten spielen. Eine Dysregulation dopaminerger Neurotransmission, speziell die veränderte Belohnungsverarbeitung, spielt eine zentrale Rolle in der Ätiopathogenese der Aufmerksamkeitsdefizit- und Hyperaktivitätsstörung (ADHS), die im Erwachsenenalter häufig durch Komorbiditäten wie affektive Störungen, Angststörungen, Substanzgebrauch-Störungen, Persönlichkeitsstörungen oder Adipositas geprägt ist. Im Rahmen einer Teilstudie eines multizentrischen europäischen Projekts, CoCA (englisch: Comorbid Conditions in ADHD) genannt, soll die Modulation des dopaminergen Belohnungssystems bei gesunden Probanden durch einen pharmakologischen Provokationstest geprüft werden. Die funktionelle Magnetresonanztomographie (MRT) stellt hierbei ein nützliches bildgebendes Verfahren dar, das nicht-invasiv und bei hoher örtlicher Auflösung Veränderungen des sogenannten BOLD-Signals (englisch: blood oxygen level dependent) misst.
Die vorliegende Arbeit untersucht, inwiefern das dopaminerge Belohnungssystem durch einen pharmakologischen Provokationstest mit einem Dopaminagonisten sowie einem Dopaminantagonisten im Vergleich zu Placebo zu modulieren ist. Dazu wurde die BOLD-Antwort mittels funktionellem MRT während eines Gewinnspiels (Monetary Incentive Delay Tasks) mit inbegriffener Antizipations- und Feedback-Phase erforscht. Es wurde zuvor postuliert, dass sich die Aktivität belohnungsabhängiger Strukturen (wie ventrales Striatum, Putamen, Caudatus, anteriore Insula und medialer präfrontaler Kortex) während des Monetary Incentive Delay Tasks in einem pharmakologisch neutralen Haupteffekt reproduzieren lässt. Außerdem wurde ein Unterschied im Aktivitätsniveau des Belohnungssystems unter Pharmaka-Administration versus Placebo erwartet, sodass unter Amisulprid eine Dämpfung, und unter Levodopa eine Aktivitätssteigerung dessen darstellbar werden sollte.
Ein kontrolliert randomisiertes, doppelblindes Cross-over-Studiendesign, umfasste 45 gesunde Probanden, die durchschnittlich circa 23 Jahre alt (SD = 2,71 Jahre) waren. Die Studienteilnehmer absolvierten einen pharmakologischen Provokationstest mit Levodopa (100mg/ 25mg Carbidopa), Amisulprid (200mg) und Placebo sowie anschließender fMRT-Messung in einem 3 Tesla Scanner in randomisierter Reihenfolge. Die Analyse der fMRT-Daten erfolgte anhand von zwei primär definierten Kontrasten: Antizipation Gewinnbedingung > Feedback Gewinnbedingung und Antizipation Gewinnbedingung > Antizipation Kontrollbedingung zur Untersuchung von Belohnungserwartung und Feedback mittels der gemessenen BOLD-Antworten. Das verwendete GewinnspielParadigma, Monetary Incentive Delay Task genannt, erlaubt hierbei eine Beobachtung verschiedener Anteile der Belohnungsverarbeitung.
Im Haupteffekt der beiden Kontraste konnte eine signifikante BOLD-Aktivität in belohnungsabhängigen Gehirnregionen wie Putamen, anteriore Insula und Thalamus dargestellt werden. Unter Amisulprid-Administration konnte ein signifikanter dämpfender Effekt im Vergleich zu Placebo gezeigt werden. Für Levodopa ergab sich wider Erwarten jedoch kein signifikanter Unterschied im Aktivitätsniveau des Belohnungssystems.
Die vorhandenen Ergebnisse der durchgeführten Studie bieten eine Basis, die veränderte Regulation dopaminerger Neurotransmission im Rahmen psychiatrischer Erkrankungen besser zu beurteilen und weiter zu erforschen. Um ADHS mit seinen Komorbiditäten umfänglicher zu erfassen, ist es unvermeidbar, den Pathomechanismus der Dysregulation dopaminerger Neurotransmission, mit der daraus folgenden veränderten Belohnungsverarbeitung, in zukünftigen Studien genauer zu untersuchen.
Suicide represents a major challenge to public mental health. In order to provide empirical evidence for prevention strategies, we hypothesized current levels of low socioeconomic status (SES) and high social isolation (SI) to be linked to increased suicide rates in N = 390 administrative districts since SES and SI are associated with mental illness. Effects of SES on suicide rates were further expected to be especially pronounced in districts with individuals showing high SI levels as SI reduces the reception of social support and moderates the impact of low SES on poor mental health. We linked German Microcensus data to register data on all 149,033 German suicides between 1997 and 2010 and estimated Prentice and Sheppard’s model for aggregate data to test the hypotheses, accounting for spatial effect correlations. The findings reveal increases in district suicide rates by 1.20% (p < 0.035) for 1% increases of district unemployment, suicide rate decreases of −0.39% (p < 0.028) for 1% increases in incomes, increases of 1.65% (p < 0.033) in suicides for 1% increases in one-person-households and increases in suicide rates of 0.54% (p < 0.036) for 1% decreases in single persons’ incomes as well as suicide rate increases of 3.52% (p < 0.000) for 1% increases in CASMIN scores of individuals who moved throughout the year preceding suicide. The results represent appropriate starting points for the development of suicide prevention strategies. For the definition of more precise measures, future work should focus on the causal mechanisms resulting in suicidality incorporating individual level data.
Molecular analysis of the ribosome recycling factor ABCE1 bound to the 30S post-splitting complex
(2020)
Ribosome recycling by the twin-ATPase ABCE1 is a key regulatory process in mRNA translation and surveillance and in ribosome-associated protein quality control in Eukarya and Archaea. Here, we captured the archaeal 30S ribosome post-splitting complex at 2.8 Å resolution by cryo-electron microscopy. The structure reveals the dynamic behavior of structural motifs unique to ABCE1, which ultimately leads to ribosome splitting. More specifically, we provide molecular details on how conformational rearrangements of the iron–sulfur cluster domain and hinge regions of ABCE1 are linked to closure of its nucleotide-binding sites. The combination of mutational and functional analyses uncovers an intricate allosteric network between the ribosome, regulatory domains of ABCE1, and its two structurally and functionally asymmetric ATP-binding sites. Based on these data, we propose a refined model of how signals from the ribosome are integrated into the ATPase cycle of ABCE1 to orchestrate ribosome recycling.
Obtaining sufficient numbers of functional natural killer (NK) cells is crucial for the success of NK-cell-based adoptive immunotherapies. While expansion from peripheral blood (PB) is the current method of choice, ex vivo generation of NK cells from hematopoietic stem and progenitor cells (HSCs) may constitute an attractive alternative. Thereby, HSCs mobilized into peripheral blood (PB-CD34+) represent a valuable starting material, but the rather poor and donor-dependent differentiation of isolated PB-CD34+ cells into NK cells observed in earlier studies still represents a major hurdle. Here, we report a refined approach based on ex vivo culture of PB-CD34+ cells with optimized cytokine cocktails that reliably generates functionally mature NK cells, as assessed by analyzing NK-cell-associated surface markers and cytotoxicity. To further enhance NK cell expansion, we generated K562 feeder cells co-expressing 4-1BB ligand and membrane-anchored IL-15 and IL-21. Co-culture of PB-derived NK cells and NK cells that were ex-vivo-differentiated from HSCs with these feeder cells dramatically improved NK cell expansion, and fully compensated for donor-to-donor variability observed during only cytokine-based propagation. Our findings suggest mobilized PB-CD34+ cells expanded and differentiated according to this two-step protocol as a promising source for the generation of allogeneic NK cells for adoptive cancer immunotherapy.
Background: High doses of capsaicin are recommended for the treatment of neuropathic pain. However, low doses evoke mechanical hypersensitivity. Activation of the capsaicin chemosensor transient receptor potential vanilloid 1 (TRPV1) induces neurogenic inflammation. In addition to the release of pro-inflammatory mediators, reactive oxygen species are produced. These highly reactive molecules generate oxidised phospholipids and 4-hydroxynonenal (4-HNE) which then directly activate TRP ankyrin 1 (TRPA1). The apolipoprotein A-I mimetic peptide D-4F neutralises oxidised phospholipids. Here, we asked whether D-4F ameliorates neurogenic hypersensitivity in rodents by targeting reactive oxygen species and 4-HNE in the capsaicin-evoked pain model.
Results: Co-application of D-4F ameliorated capsaicin-induced mechanical hypersensitivity and allodynia as well as persistent heat hypersensitivity measured by Randell–Selitto, von Frey and Hargreaves test, respectively. In addition, mechanical hypersensitivity was blocked after co-injection of D-4F with the reactive oxygen species analogue H2O2 or 4-HNE. In vitro studies on dorsal root ganglion neurons and stably transfected cell lines revealed a TRPA1-dependent inhibition of the calcium influx when agonists were pre-incubated with D-4F. The capsaicin-induced calcium influx in TRPV1-expressing cell lines and dorsal root ganglion neurons sustained in the presence of D-4F.
Conclusions: D-4F is a promising compound to ameliorate TRPA1-dependent hypersensitivity during neurogenic inflammation.
In dieser Arbeit wurde die Messung des Flusses von Protonen in Silber-Silber-Kollisionen bei 1:58 AGeV beschrieben. Dabei wurden drei verschiedene Flow Koeffzienten betrachtet, der gerichtete, der elliptische sowie der dreieckige Fluss.
Nachdem die Protonen zunächst anhand ihrer Masse identifziert wurden, wurde die Reaktionsebene rekonstruiert. Nachfolgend wurde das Vorgehen zur Bestimmmung der ersten drei Flow-Koeffzienten v1, v2 und v3 beschrieben. Diese wurden anschließend in Abhäangigkeit des Transversalimpulses und der Rapidität für vier Zentralitätsklassen im Bereich von 0 - 40% Zentralität dargestellt.
Da die Daten ebenfalls Silber-Kohlenstoff Reaktionen enthalten, weisen die Spektren eine Abweichung vom erwarteten Verlauf auf. Daher wurden diese Reaktionen anhand des in Abschnitt 3.1 beschriebenen Energieverhältnisses ERAT abgeschätzt und mit Hilfe eines Cut-Off Werts ausgeschlossen. Die daraus resultierenden Spektren konnten dadurch verbessert werden.
Im Fall der Gold-Gold Strahlzeit aus dem Jahr 2012 konnten neben Daten der hier diskutierten Flow-Koeffzienten v1, v2 und v3 ebenfalls Koeffzienten höherer Ordnung, v4 und v5, sowie Hinweise auf ein Auftreten von v6 gefunden werden.
Ähnliche Analysen könnten im Fall der Daten der Silber-Silber Kollisionen durchgeführt werden. Hier tritt zwar ein quantitativ kleinerer Fluss auf, da es sich bei den kollidierenden Nuklei um ein kleineres System handelt, jedoch treten im Vergleich zu Gold-Gold Kollisionen etwa zweifach so hohe Event-Raten auf. Somit kann mit der in dieser Arbeit beschriebenen Herangehensweise unter Verwendung der Daten der gesamten Strahlzeit untersucht werden, ob Hinweise auf Flow-Koeffzienten höherer Ordnung zu finden sind.
Außerdem sollte bei den bestehenden Ergebnissen eine Korrektur des Effekts der Occupancy des Detektors durchgeführt werden, da dieser wie in Abschnitt 3.2.1 beschrieben zu Verfälschungen des gemessenen Flusses führt. Dieser Effekt wird insbesondere im Fall des gerichteten Flusses v1 deutlich.
Des Weiteren ist eine Abschätzung der systematischen Fehler der Messungen erforderlich.
Dafür kann untersucht werden, welche Auswahlkriterien und Parameter die Messung beeinflussen, beispielsweise die Spurrekonstruktion und -selektion oder die Teilchenidentifikation. Unter Betrachtung der Auswirkungen auf die Ergebnisse der Flow-Koeffzienten kann die Analyse daraufhin mit Variationen dieser Werte durchgeführt werden. Somit kann der Bereich der systematischen Fehler abgeschätzt werden.
Ergodic subspace analysis
(2020)
Properties of psychological variables at the mean or variance level can differ between persons and within persons across multiple time points. For example, cross-sectional findings between persons of different ages do not necessarily reflect the development of a single person over time. Recently, there has been an increased interest in the difference between covariance structures, expressed by covariance matrices, that evolve between persons and within a single person over multiple time points. If these structures are identical at the population level, the structure is called ergodic. However, recent data confirms that ergodicity is not generally given, particularly not for cognitive variables. For example, the <i>g</i> factor that is dominant for cognitive abilities between persons seems to explain far less variance when concentrating on a single person’s data. However, other subdimensions of cognitive abilities seem to appear both between and within persons; that is, there seems to be a lower-dimensional subspace of cognitive abilities in which cognitive abilities are in fact ergodic. In this article, we present ergodic subspace analysis (ESA), a mathematical method to identify, for a given set of variables, which subspace is most important within persons, which is most important between person, and which is ergodic. Similar to the common spatial patterns method, the ESA method first whitens a joint distribution from both the between and the within variance structure and then performs a principle component analysis (PCA) on the between distribution, which then automatically acts as an inverse PCA on the within distribution. The difference of the eigenvalues allows a separation of the rotated dimensions into the three subspaces corresponding to within, between, and ergodic substructures. We apply the method to simulated data and to data from the COGITO study to exemplify its usage.
Objectives: The aim of this study was to investigate the relationship between anamnestic, axiographic and occlusal parameters and postural control in healthy women aged between 41 and 50 years. Materials and methods: A total of 100 female participants aged between 41 and 50 (45.12 ± 2.96) years participated in the study. In addition to completing a general anamnesis questionnaire, lower jaw movements were measured axiographically, dental occlusion parameters were determined using a model analysis and postural parameters were recorded using a pressure measurement platform. The significance level was 5%. Results: An increasing weight and a rising BMI lead to a weight shifted from the rearfoot (p ≤ 0.01/0.04) to the forefoot (p ≤ 0.01/0.02). A limited laterotrusion on the right resulted in a lower forefoot load and an increased rearfoot load (p ≤ 0.01). Laterotrusion to the left (extended above the standard) showed a lower frontal sway (p ≤ 0.02) and a reduced elliptical area, height and width (p ≤ 0.01, 0.02, 0.03). Thus, the extent of deviation correlated with reduced right forefoot loading (p ≤ 0.03) and the extent of deflection correlated with increased left foot loading (p ≤ 0.01). The higher the extent of angle class II malocclusion, the larger the ellipse area (p ≤ 0.04) and the ellipse height (p ≤ 0.02) resulted. Conclusions: There is a connection between weight, BMI and laterotrusion, as well as between angle class II malocclusion and postural control in women aged between 41 and 50 years. Interdisciplinary functional examinations of mandibular movements treating possible limitations can be conducive for an improvement of postural control. Clinical relevance: Angle class II malocclusion has a negative influence on postural control.
The occupation of dental assistants (DAs) involves many health risks of the musculoskeletal system due to static and prolonged work, which can lead to musculoskeletal disorders (MSDs). The aim of the study was to investigate the prevalence of MSDs in DAs in Germany. Methods: For this purpose, an online questionnaire analyzed 406 (401 female participants and 5 male participants, 401w/5m) DAs. It was based on the Nordic Questionnaire (lifetime, 12-month, and seven-day MSDs’ prevalence separated into neck, shoulder, elbow, wrist, upper back, lower back, hip, knee, and ankle), and occupational and sociodemographic questions as well as questions about specific medical conditions. Results: 98.5% of the participants reported complaints of at least one body region in their lives, 97.5% reported at least one complaint in the last 12 months and 86.9% affirmed at least one complaint in the last seven days. For lifetime, 12-month and seven-day prevalence, the neck was the region that was most affected followed by the shoulder, the upper back and the lower back. Conclusion: The prevalence of MSDs among German (female) DAs was very high. The most affected area is the neck, followed by the shoulder, the lower back, and the upper back. It, therefore, seems necessary to devote more attention to ergonomics at the working practice of DAs as well in education and in dental work.
Background: The aim of this study was to collect standard reference values of the weight and the maximum pressure distribution in healthy adults aged 18–65 years and to investigate the influence of constitutional parameters on it.
Methods: A total of 416 healthy subjects (208 male / 208 female) aged between 18 and 65 years (Ø 38.3 ± 14.1 years) participated in this study, conducted 2015–2019 in Heidelberg. The age-specific evaluation is based on 4 age groups (G1, 18–30 years; G2, 31–40 years; G3, 41–50 years; G4, 51–65 years). A pressure measuring plate FDM-S (Zebris/Isny/Germany) was used to collect body weight distribution and maximum pressure distribution of the right and left foot and left and right forefoot/rearfoot, respectively.
Results: Body weight distribution of the left (50.07%) and right (50.12%) foot was balanced. There was higher load on the rearfoot (left 54.14%; right 55.09%) than on the forefoot (left 45.49%; right 44.26%). The pressure in the rearfoot was higher than in the forefoot (rearfoot left 9.60 N/cm2, rearfoot right 9.51 N/cm2/forefoot left 8.23 N/cm2, forefoot right 8.59 N/cm2). With increasing age, the load in the left foot shifted from the rearfoot to the forefoot as well as the maximum pressure (p ≤ 0.02 and 0.03; poor effect size). With increasing BMI, the body weight shifted to the left and right rearfoot (p ≤ 0.001, poor effect size). As BMI increased, so did the maximum pressure in all areas (p ≤ 0.001 and 0.03, weak to moderate effect size). There were significant differences in weight and maximum pressure distribution in the forefoot and rearfoot in the different age groups, especially between younger (18–40 years) and older (41–65 years) subjects.
Discussion: Healthy individuals aged from 18 to 65 years were found to have a balanced weight distribution in an aspect ratio, with a 20% greater load of the rearfoot. Age and BMI were found to be influencing factors of the weight and maximum pressure distribution, especially between younger and elder subjects. The collected standard reference values allow comparisons with other studies and can serve as a guideline in clinical practice and scientific studies.
Background: Musculoskeletal disorders (MSD) are common among dental professionals. The most common areas affected are the trunk, neck, shoulders and wrists. Current evidence suggests that the causes of MSD can be found in the physical demands of the profession. Posture and movement during treatment is influenced by the arrangement of the treatment concept (patient chair, equipment and cabinets). It has not been investigated whether the ergonomic risk differs between the treatment concepts.
Methods: To evaluate the prevalence of MSD in dental professionals, 1000 responses will be collected from a nationwide (Germany) online questionnaire (mod. Nordic Questionnaire and mod. Meyer questionnaire). In order to assess the ergonomic risk of the treatment techniques used in the four treatment concepts, 3D movement analyses are carried out with inertial sensors. For this purpose, 20 teams of dentists and dental assistants from four dental fields of specializations (generalists, orthodontists, endodontists and oral surgeons) and a student control group will be recruited. Each team will execute field specific standardized treatments at a dummy head. Measurements are carried out in each of the four treatment concepts. The data will be analyzed using the Rapid Upper Limb Assessment (RULA) which will be modified for the evaluation of objective data.
Conclusions: On the basis of these investigations, a substantial gain of knowledge regarding work-related MSD in the field of dentistry and its potential biomechanical causes is possible. For the first time, objective and differentiated comparisons between the four treatment concepts are possible for different fields of dental specialization. Up to now, statically held positions of the trunk and proximal upper extremities, but also the repetitive movements of the hands have been considered a risk for MSD. Since both are included in the RULA, dental activities can be assessed in a detailed but also global manner with regard to ergonomic risks.
Background: Dentists are at a higher risk of suffering from musculoskeletal disorders (MSD) than the general population. However, the latest study investigating MSD in the dental profession in Germany was published about 20 years ago. Therefore, the aim of this study was to reveal the current prevalence of MSD in dentists and dental students in Germany. Methods: The final study size contained 450 (287 f/163 m) subjects of different areas of specialization. The age of the participants ranged from 23 to 75 years. The questionnaire consisted of a modified version of the Nordic Questionnaire, work-related questions from the latest questionnaire of German dentists, typical medical conditions and self-developed questions. Results: The overall prevalence showed that dentists suffered frequently from MSD (seven days: 65.6%, twelve months: 92%, lifetime: 95.8%). The most affected body regions included the neck (42.7%–70.9%–78.4%), shoulders (29.8%–55.6%–66.2%) and lower back (22.9%–45.8%–58.7%). Overall, female participants stated that they suffered from pain significantly more frequently, especially in the neck, shoulders and upper back. Conclusion: The prevalence of MSD among dentists, especially in the neck, shoulder and back area, was significantly higher than in the general population. In addition, women suffered more frequently from MSD than men in almost all body regions.
Background: To detect deviations from a normal postural control, standard values can be helpful for comparison purposes. Since the postural control is influenced by gender and age, the aim of the present study was the collection of standard values for women between 31 and 40 years of age.
Methods: For the study, 106 female, subjectively healthy, German subjects aged between 31 and 40 years (35 ± 2.98 years) were measured using a pressure measuring platform.
Results: Their average BMI was 21.60 ± 4.65 kg/m2. The load distribution between left and right foot was almost evenly balanced with a median 51.46% load on the left [tolerance interval (TR) 37.02%/65.90%; confidence interval (CI) 50.06/52.85%] and 48.54% [TR 43.10/62.97%; CI 47.14/49.93%] on the right foot. The median forefoot load was 33.84% [TR 20.68/54.73%; CI 31.67/37.33%] and the rearfoot load was measured at 66.16% [TR 45.27/79.33%; CI 62.67/68.33%]. The median/mean body sway in the sagittal plane was measured 12 mm [TR 5.45/23.44 mm; CI 11.00/14.00 mm] and 8.17 mm in the frontal plane [TR 3.33/19.08 mm; CI 7.67/9.33 mm]. The median of the ellipse area is 0.72 cm2 [TR 0.15/3.69 cm2; CI 0.54/0.89°]. The ellipse width has a median of 0.66 cm [TR 0.30/1.77 cm; CI 0.61/0.78 cm] and the height of 0.33 cm [TR 0.13/0.71 cm; CI 0.30/0.37 cm]. The ellipse angle (sway, left forefoot to right rearfoot) has a mean of − 19.34° [TR − 59.21/− 0.44°; CI − 22.52/− 16.16°] and the ellipse angle sway from right forefoot to left rearfoot has a mean of 12.75° [TR 0.09/59.09°; CI 9.00/16.33°].
Conclusion: The right-to-left ratio is balanced. The forefoot-to-rearfoot ratio is approximately 1:2. Also, the body sway can be classified with 12 and 8 mm as normal. The direction of fluctuation is either approx. 19° from the left forefoot to the right rearfoot or approx. 13° the opposite. Body weight, height, and BMI were comparable to the German average of women in a similar age group, so that the measured standard values are representative and might serve as baseline for the normal function of the balance system in order to support the diagnosis of possible dysfunctions in postural control.
The hot and dense QCD matter produced in nuclear collisions at ultrarelativistic energy is characterized by very intense electromagnetic fields which attain their maximal strength in the early pre-equilibrium stage and interplay with the strong vorticity induced in the plasma by the large angular momentum of the colliding system. A promising observable keeping trace of these phenomena is the directed flow of light hadrons and heavy mesons produced in symmetric and asymmetric heavy-ion collisions as well as in proton-induced reactions. In particular, the splitting of the directed flow between particles with the same mass but opposite electric charge as a function of rapidity and transverse momentum gives access to the electromagnetic response of medium in all collision stages and in the different colliding systems. The highest influence of the electromagnetic fields is envisaged in the pre-equilibrium stage of the collision and therefore a significant imprint is left on the early-produced heavy quarks. The aim of this review is to discuss the current developments towards the understanding of the generation and relaxation time of the electromagnetic fields embedded in both large and small systems and their impact on the charge-odd directed flow of light and heavy particles, highlighting the experimental results and the different theoretical approaches. Since it is possible to perform realistic simulations of high-energy collisions that incorporate also the generated electromagnetic fields and vorticity, the study of the directed flow can provide unique insight into the early nonequilibrium phase and the ensuing QGP formation and transport properties.
A new method of event characterization based on Deep Learning is presented. The PointNet models can be used for fast, online event-by-event impact parameter determination at the CBM experiment. For this study, UrQMD and the CBM detector simulation are used to generate Au+Au collision events at 10 AGeV which are then used to train and evaluate PointNet based architectures. The models can be trained on features like the hit position of particles in the CBM detector planes, tracks reconstructed from the hits or combinations thereof. The Deep Learning models reconstruct impact parameters from 2-14 fm with a mean error varying from -0.33 to 0.22 fm. For impact parameters in the range of 5-14 fm, a model which uses the combination of hit and track information of particles has a relative precision of 4-9% and a mean error of -0.33 to 0.13 fm. In the same range of impact parameters, a model with only track information has a relative precision of 4-10% and a mean error of -0.18 to 0.22 fm. This new method of event-classification is shown to be more accurate and less model dependent than conventional methods and can utilize the performance boost of modern GPU processor units.
Zinc finger proteins (ZNF) are a large group of transcription factors with diverse functions. We recently discovered that endothelial cells harbour a specific mechanism to limit the action of ZNF354C, whose function in endothelial cells is unknown. Given that ZNF354C has so far only been studied in bone and tumour, its function was determined in endothelial cells. ZNF354C is expressed in vascular cells and localises to the nucleus and cytoplasm. Overexpression of ZNF354C in human endothelial cells results in a marked inhibition of endothelial sprouting. RNA-sequencing of human microvascular endothelial cells with and without overexpression of ZNF354C revealed that the protein is a potent transcriptional repressor. ZNF354C contains an active KRAB domain which mediates this suppression as shown by mutagenesis analysis. ZNF354C interacts with dsDNA, TRIM28 and histones, as observed by proximity ligation and immunoprecipitation. Moreover, chromatin immunoprecipitation revealed that the ZNF binds to specific endothelial-relevant target-gene promoters. ZNF354C suppresses these genes as shown by CRISPR/Cas knockout and RNAi. Inhibition of endothelial sprouting by ZNF354C is dependent on the amino acids DV and MLE of the KRAB domain. These results demonstrate that ZNF354C is a repressive transcription factor which acts through a KRAB domain to inhibit endothelial angiogenic sprouting.
Neutron capture on 241Am plays an important role in the nuclear energy production and also provides valuable information for the improvement of nuclear models and the statistical interpretation of the nuclear properties. A new experiment to measure the 241Am(n, γ) cross section in the thermal region and the first few resonances below 10 eV has been carried out at EAR2 of the n_TOF facility at CERN. Three neutron-insensitive C6D6 detectors have been used to measure the neutron-capture gamma cascade as a function of the neutron time of flight, and then deduce the neutron capture yield. Preliminary results will be presented and compared with previously obtained results at the same facility in EAR1. In EAR1 the gamma-ray background at thermal energies was about 90% of the signal while in EAR2 is up to a 25 factor much more favorable signal to noise ratio. We also extended the low energy limit down to subthermal energies. This measurement will allow a comparison with neutron capture measurements conducted at reactors and using a different experimental technique.
Im Rahmen der Serie „Biomarker“, die im Zentralblatt für Arbeitsmedizin und Ergonomie publiziert wird, ist das Angiotensin-Converting Enzyme (ACE) zugehörig als häufiger Marker in der Diagnostik von pulmonalen und extrapulmonalen Erkrankungen. Die Bestimmung von ACE stellt einen wesentlichen Bestandteil der Diagnostik von pulmonalen und extrapulmonalen Erkrankungen dar. Der Einfluss von Tabakkonsum, Medikamenten, Zink-Chelatoren auf die ACE-Konzentration wird eruiert. ACE erwies sich als Marker mit einer hohen Sensitivität und Spezifität bei Lungenerkrankungen.
Neuropathic pain, a form of chronic pain, is a steadily rising health problem due to health costs and increasing numbers of patients. Neuropathic pain conditions arise upon metabolic disorders, infections, chemotherapeutic treatment, trauma or nerve injury. Especially nerve injury induced neuropathic pain is characterized by spontaneous or ongoing pain due to neuroimmune interactions. Thereby, inflammatory mediators, released by the injured nerve, recruit to and activate immune cells at the site of injury. Those mediators further activate transient receptor potential vanilloid 1 (TRPV1), a known channel involved in pain perception, or bind to G-protein coupled receptors (GPCR) in peripheral nerve endings. The following activated second messenger signaling pathways lead to sensitization of TRPV1. One of those GPCRs is G2A.
The overall aim of this thesis was to investigate the role of G2A in nerve-injury induced neuropathic pain. For this, the common mouse model of nerve-injury induced neuropathic pain, the spared-nerve injury, was used. As measurements with dynamic plantar aesthesiometer showed, G2A-deficiency leads to reduced mechanical hypersensitivity. Upon analysis with FACS, ELISA and Luminex a reduced number of macrophages and neutrophils at the injured nerve, as well as less inflammatory mediators (TNFα, IL-6, VEGF) in G2A-deficient animals was observed. In dorsal root ganglia (DRGs) there was only a reduced number of macrophages and less IL-12 observed in G2A-deficient animals. Additionally, in wild-type mice, G2A agonist 9-HODE was elevated at the injured nerve, as a LC-MS/MS analysis showed.
To investigate the underlying pathways of G2A-9-HODE signaling, a proteom screen was performed. This screen revealed upregulation of multiple proteins involved in migration in wild-type macrophages. Additionally, Ca-Imaging and transwell migration assays showed that the G2A antagonist G2A11, had desensitizing effects on DRG neurons and inhibited macrophage migration.
Overall, the results suggest that loss of G2A has dual effects. On the one hand loss of G2A is antinociceptive. On the other hand, G2A-deficiency leads to reduced inflammation, suggesting G2A as promising target in treatment of neuropathic pain. Here, an antagonist had inhibitory effects on the migration and the sensitization.
Der politikgeschichtlich orientierte Aufsatz untersucht das Verhältnis Ricimers zu den während seiner Amtszeit als magister militum regierenden weströmischen Kaisern. Insbesondere fragt er danach, inwiefern Ricimer zum Fall des weströmischen Kaisertums beigetragen hat. Neben den antiken Quellen stützt sich der Aufsatz auf ältere und jüngste Forschungsliteratur (insbesondere Anders 2010 und folgende Arbeiten). Er zeigt Forschungskontroversen auf und eröffnet am Schluss weitergehende Perspektiven der Forschung zu den Heermeistern des fünften Jahrhunderts.
The in vivo firing patterns of ventral midbrain dopamine neurons are controlled by afferent and intrinsic activity to generate sensory cue and prediction error signals that are essential for reward-based learning. Given the absence of in vivo intracellular recordings during the last three decades, the subthreshold membrane potential events that cause changes in dopamine neuron firing patterns remain unknown. To address this, we established in vivo whole-cell recordings and obtained over 100 spontaneously active, immunocytochemically-defined midbrain dopamine neurons in isoflurane-anaesthetized adult mice. We identified a repertoire of subthreshold membrane potential signatures associated with distinct in vivo firing patterns. Dopamine neuron activity in vivo deviated from single-spike pacemaking by phasic increases in firing rate via two qualitatively distinct biophysical mechanisms: 1) a prolonged hyperpolarization preceding rebound bursts, accompanied by a hyperpolarizing shift in action potential threshold; and 2) a transient depolarization leading to high-frequency plateau bursts, associated with a depolarizing shift in action potential threshold. Our findings define a mechanistic framework for the biophysical implementation of dopamine neuron firing patterns in the intact brain.
The firing pattern of ventral midbrain dopamine neurons is controlled by afferent and intrinsic activity to generate prediction error signals that are essential for reward-based learning. Given the absence of intracellular in vivo recordings in the last three decades, the subthreshold membrane potential events that cause changes in dopamine neuron firing patterns remain unknown. By establishing stable in vivo whole-cell recordings of >100 spontaneously active midbrain dopamine neurons in anaesthetized mice, we identified the repertoire of subthreshold membrane potential signatures associated with distinct in vivo firing patterns. We demonstrate that dopamine neuron in vivo activity deviates from a single spike pacemaker pattern by eliciting transient increases in firing rate generated by at least two diametrically opposing biophysical mechanisms: a transient depolarization resulting in high frequency plateau bursts associated with a reactive, depolarizing shift in action potential threshold; and a prolonged hyperpolarization preceding slower rebound bursts characterized by a predictive, hyperpolarizing shift in action potential threshold. Our findings therefore illustrate a framework for the biophysical implementation of prediction error and sensory cue coding in dopamine neurons by tuning action potential threshold dynamics.
Background: The spontaneously diabetic “non-obese diabetic” (NOD) mouse is a faithful model of human type-1 diabetes (T1D). Methods: Given the pivotal role of α4 integrin (CD49d) in other autoimmune diseases, we generated NOD mice with α4-deficient hematopoiesis (NOD.α4-/-) to study the role of α4 integrin in T1D. Results: NOD.α4-/- mice developed islet-specific T-cells and antibodies, albeit quantitatively less than α4+ counterparts. Nevertheless, NOD.α4-/- mice were completely and life-long protected from diabetes and insulitis. Moreover, transplantation with isogeneic α4-/- bone marrow prevented progression to T1D of pre-diabetic NOD.α4+ mice despite significant pre-existing islet cell injury. Transfer of α4+/CD3+, but not α4+/CD4+ splenocytes from diabetic to NOD.α4-/- mice induced diabetes with short latency. Despite an only modest contribution of adoptively transferred α4+/CD3+ cells to peripheral blood, pancreas-infiltrating T-cells were exclusively graft derived, i.e., α4+. Microbiota of diabetes-resistant NOD.α4-/- and pre-diabetic NOD.α4+ mice were identical. Co- housed diabetic NOD.α4+ mice showed the characteristic diabetic dysbiosis, implying causality of diabetes for dysbiosis. Incidentally, NOD.α4-/- mice were protected from autoimmune sialitis. Conclusion: α4 is a potential target for primary or secondary prevention of T1D.
Cell-free expression represents an attractive method to produce large quantities of selectively labeled protein for NMR applications. Here, cell-free expression was used to label specific regions of the growth hormone secretagogue receptor (GHSR) with NMR-active isotopes. The GHSR is a member of the class A family of G protein-coupled receptors. A cell-free expression system was established to produce the GHSR in the precipitated form. The solubilized receptor was refolded in vitro and reconstituted into DMPC lipid membranes. Methionines, arginines, and histidines were chosen for 13C-labeling as they are representative for the transmembrane domains, the loops and flanking regions of the transmembrane α-helices, and the C-terminus of the receptor, respectively. The dynamics of the isotopically labeled residues was characterized by solid-state NMR measuring motionally averaged 1H-13C dipolar couplings, which were converted into molecular order parameters. Separated local field DIPSHIFT experiments under magic-angle spinning conditions using either varying cross polarization contact times or direct excitation provided order parameters for these residues showing that the C-terminus was the segment with the highest motional amplitude. The loop regions and helix ends as well as the transmembrane regions of the GHSR represent relatively rigid segments in the overall very flexible receptor molecule. Although no site resolution could be achieved in the experiments, the previously reported highly dynamic character of the receptor concluded from uniformly 13C labeled receptor samples could be further specified by this segmental labeling approach, leading to a more diversified understanding. of the receptor dynamics under equilibrium conditions
DNA methylation was shown previously to be a crucial mechanism responsible for transcriptional deregulation in the pathogenesis of classical Hodgkin lymphoma (cHL). To identify epigenetically inactivated miRNAs in cHL, we have analyzed the set of miRNAs downregulated in cHL cell lines using bisulfite pyrosequencing. We focused on miRNAs with promoter regions located within or <1000 bp from a CpG island. Most promising candidate miRNAs were further studied in primary Hodgkin and Reed-Sternberg (HRS) cells obtained by laser capture microdissection. Last, to evaluate the function of identified miRNAs, we performed a luciferase reporter assay to confirm miRNA: mRNA interactions and therefore established cHL cell lines with stable overexpression of selected miRNAs for proliferation tests. We found a significant reverse correlation between DNA methylation and expression levels of mir-339-3p, mir-148a-3p, mir-148a-5p and mir-193a-5 demonstrating epigenetic regulation of these miRNAs in cHL cell lines. Moreover, we demonstrated direct interaction between miR-148a-3p and IL15 and HOMER1 transcripts as well as between mir-148a-5p and SUB1 and SERPINH1 transcripts. Furthermore, mir-148a overexpression resulted in reduced cell proliferation in the KM-H2 cell line. In summary, we report that mir-148a is a novel tumor suppressor inactivated in cHL and that epigenetic silencing of miRNAs is a common phenomenon in cHL.
The main goal of the present study was the identification of cellular phenotypes in attention-deficit-/hyperactivity disorder (ADHD) patient-derived cellular models from carriers of rare copy number variants (CNVs) in the PARK2 locus that have been previously associated with ADHD. Human-derived fibroblasts (HDF) were cultured and human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into dopaminergic neuronal cells (mDANs). A series of assays in baseline condition and in different stress paradigms (nutrient deprivation, carbonyl cyanide m-chlorophenyl hydrazine (CCCP)) focusing on mitochondrial function and energy metabolism (ATP production, basal oxygen consumption rates, reactive oxygen species (ROS) abundance) were performed and changes in mitochondrial network morphology evaluated. We found changes in PARK2 CNV deletion and duplication carriers with ADHD in PARK2 gene and protein expression, ATP production and basal oxygen consumption rates compared to healthy and ADHD wildtype control cell lines, partly differing between HDF and mDANs and to some extent enhanced in stress paradigms. The generation of ROS was not influenced by the genotype. Our preliminary work suggests an energy impairment in HDF and mDAN cells of PARK2 CNV deletion and duplication carriers with ADHD. The energy impairment could be associated with the role of PARK2 dysregulation in mitochondrial dynamics.
Never good enough: the relation between the impostor phenomenon and multidimensional perfectionism
(2020)
The Impostor Phenomenon can be described as the tendency to attribute professional success not to one’s own abilities but to excessive effort or fortunate external circumstances. Individuals strongly experiencing those tendencies fear that one day they will be exposed as “impostors” as soon as their alleged incompetence can no longer be concealed. Typical characteristics of the Impostor Phenomenon outlined by Clance (1985) show a remarkable conceptual similarity to the personality construct of perfectionism. Thus, the present study aimed at investigating how the Impostor Phenomenon is related to various facets of dispositional perfectionism with respect to predominant conceptualizations of perfectionism by Frost et al. (1990), Hewitt and Flett (1991), as well as their combination within the bifactor model of Perfectionistic Strivings and Perfectionistic Concerns (Frost et al. 1993). A total of N = 274 individuals participated in an online survey including the Impostor Phenomenon Scale (CIPS; Clance 1988), the Frost Multidimensional Perfectionism Scale (FMPS; Frost et al. 1990), and the Hewitt und Flett Multidimensional Perfectionism Scale (MPS short form; Hewitt et al. 2008). Hierarchical regression analyses were conducted to determine the differential contributions of perfectionism dimensions and factors in predicting the Impostor Phenomenon. The perfectionism dimensions Doubts about Actions, Concern over Mistakes and Socially prescribed Perfectionism appeared to be efficient predictors of the Impostor Phenomenon. Contrary to Perfectionistic Strivings, Perfectionistic Concerns as a maladaptive perfectionism factor strongly contributed to the prediction of the Impostor Phenomenon. Theoretical and practical implications of the associations between the Impostor Phenomenon and multidimensional perfectionism are discussed.
We explore the phase structure of the 1+1 dimensional Gross-Neveu model at finite number of fermion flavors using lattice field theory. Besides a chirally symmetric phase and a homogeneously broken phase we find evidence for the existence of an inhomogeneous phase, where the condensate is a spatially oscillating function. Our numerical results include a crude μ-T phase diagram.
Ziel dieser klinischen Studie war es, die Ergebnisse der operativen Behandlung eines idiopathischen Makulaforamens durch Vitrektomie, ggf. in Kombination mit einer Phakoemulsifikation, ILM-Peeling und einer Tamponade entweder mit Luft oder mit 20%-igem SF6-Gas zu vergleichen. Primärer Endpunkt war die Verschlussrate nach einer Vitrektomie und die Reoperationsrate bei primär nicht geschlossenen Makulaforamina. Sekundärer Endpunkt war die Visusentwicklung in der ersten postoperativen Woche und nach 3 Monaten.
In der vorliegenden Arbeit wurden hierzu retrospektiv 117 Augen von 117 konsekutiven Patienten analysiert. Es wurden die Ergebnisse von 2 Patientengruppen verglichen. In der ersten Gruppe wurden 66 Augen (m=27, w=39, Altersmedian 70 Jahre), bei denen am Ende der Vitrektomie eine Tamponade mit Luft erfolgte, untersucht. In der zweiten Gruppe wurden die Ergebnisse von 51 Augen (m=20, w=31, Altersmedian 71 Jahre), bei denen 20%-SF6-Gas als Tamponade verwendet wurde, ausgewertet. Bei etwa 70 % der Augen beider Gruppen erfolgte eine simultane Phakoemulsifikation. Der Verschluss des Makulaforamens wurde bereits in den ersten postoperativen Tagen mit einem modifizierten Fourier Domain-OCT untersucht. Sobald der Verschluss des Makulaforamens im OCT gesichert werden konnte, wurde die postoperative „Gesicht nach unten“-Lagerung („Bauchlage“) beendet. Die mediane Lagerungszeit betrug 1 Tag (Spanne 1-6 Tage). Der Zeitraum der Nachbeobachtung betrug 3 Monate (Median).
Die Verschlussrate nach einer Vitrektomie aller Makulaforamina betrug 87,2% (102/117 Augen). Die primäre Verschlussrate der Luft-Gruppe und der SF6-Gas-Gruppe betrug 83,3% (55/66 Augen) bzw. 92,2% (47/51 Augen). Bei Augen mit einem persistierenden Foramen erfolgte eine frühe Reoperation. Die Verschlussrate nach 3 Monaten lag insgesamt bei 99,1% (116/117 Augen), in der Luft-Gruppe bei 98,5% (65/66 Augen) und in der SF6-Gas-Gruppe bei 100% (51/51 Augen). Es zeigte sich kein statistisch signifikanter Unterschied der Verschlussrate bzw. der anatomischen Ergebnisse zwischen den beiden Endotamponade-Gruppen.
Es konnte jedoch ein statistisch signifikanter Unterschied des Fernvisus bei der Entlassung zwischen beiden Endotamponadegruppen nachgewiesen werden. Der logMAR-Visus bei Entlassung lag in der Luft-Gruppe mit 1,3 (Median) deutlich unter dem Visus der SF6-Gas-Gruppe mit 1,9 (Median). Die Anwendung von Luft führte somit im Vergleich zu SF6 zu einem schnelleren postoperativen Visusanstieg. In beiden Gruppen zeigte sich nach 3 Monaten eine signifikante Visusbesserung. Es ließ sich kein signifikanter Unterschied des Fernvisus zwischen den beiden Gruppen mehr nachweisen.
Die Makulaforamenchirurgie mit pars plana Vitrektomie und Peeling der ILM erzielte sowohl mit einer Luft- als auch mit einer 20%-SF6-Gas-Tamponade guten anatomischen und funktionellen Ergebnissen. Mit einer kurz wirksamen Endotamponade erscheint eine postoperative Lagerung essenziell, dürfte aber in den meisten Fällen nur wenige Tage erforderlich sein, um den Verschluss eines durchgreifenden Makulaforamens zu erreichen. Die Reoperations-Rate nach einer Lufttamponade war bei sehr großen Foramina (> 600 µm) signifikant höher als bei Foramina mit einem Durchmesser kleiner 600 µm. Daher scheint die Anwendung von Gasen, die länger als Luft wirken, nur bei sehr großen Foramina erforderlich zu sein. Vorteil einer kurz wirkenden Lufttamponade ist die postoperativ um einige Tage schneller einsetzende visuelle Rehabilitation, so dass die Patienten früher in ihren Alltag zurückkehren können. Eine frühe postoperative Untersuchung der Makula unter Einsatz der optischen Kohärenztomographie ist Voraussetzung für eine individualisierte Steuerung der Lagerung und für eine möglichst frühe Erkennung und Reoperation von nicht geschlossenen Makulalöchern.
Vegetation responds to drought through a complex interplay of plant hydraulic mechanisms, posing challenges for model development and parameterization. We present a mathematical model that describes the dynamics of leaf water-potential over time while considering different strategies by which plant species regulate their water-potentials. The model has two parameters: the parameter λ describing the adjustment of the leaf water potential to changes in soil water potential, and the parameter Δψww describing the typical ‘well-watered’ leaf water potentials at non-stressed (near-zero) levels of soil water potential. Our model was tested and calibrated on 110 time-series datasets containing the leaf- and soil water potentials of 66 species under drought and non-drought conditions. Our model successfully reproduces the measured leaf water potentials over time based on three different regulation strategies under drought. We found that three parameter sets derived from the measurement data reproduced the dynamics of 53% of an drought dataset, and 52% of a control dataset [root mean square error (RMSE) < 0.5 MPa)]. We conclude that, instead of quantifying water-potential-regulation of different plant species by complex modeling approaches, a small set of parameters may be sufficient to describe the water potential regulation behavior for large-scale modeling. Thus, our approach paves the way for a parsimonious representation of the full spectrum of plant hydraulic responses to drought in dynamic vegetation models.
In order to address security and privacy problems in practice, it is very important to have a solid elicitation of requirements, before trying to address the problem. In this thesis, specific challenges of the areas of social engineering, security management and privacy enhancing technologies are analyzed:
Social Engineering: An overview of existing tools usable for social engineering is provided and defenses against social engineering are analyzed. Serious games are proposed as a more pleasant way to raise employees’ awareness and to train them.
Security Management: Specific requirements for small and medium sized energy providers are analyzed and a set of tools to support them in assessing security risks and improving their security is proposed. Larger enterprises are supported by a method to collect security key performance indicators for different subsidiaries and with a risk assessment method for apps on mobile devices. Furthermore, a method to select a secure cloud provider – the currently most popular form of outsourcing – is provided.
Privacy Enhancing Technologies: Relevant factors for the users’ adoption of privacy enhancing technologies are identified and economic incentives and hindrances for companies are discussed. Privacy by design is applied to integrate privacy into the use cases e-commerce and internet of things.
Background: Zolpidem is a non-benzodiazepine hypnotic agent which has been shown to be effective in inducing and maintaining sleep in adults and is one of the most frequently prescribed hypnotics in the world. For drugs that are used to treat sleeping disorders, the time to reach the maximum concentration (Tmax) of the drug in plasma is important to achieving a fast onset of action and this must be maintained when switching from one product to another.
Objectives: The main objective of the present work was to create a PBPK/PD model for zolpidem and establish a clinically relevant “safe space” for dissolution of zolpidem from the commercial immediate release (IR) formulation. A second objective was to analyze literature pharmacokinetic data to verify the negative food effect ascribed to zolpidem and consider its ramifications in terms of the “safe space” for dissolution.
Methods: Using dissolution, pharmacokinetic and pharmacodynamic data, an integrated PBPK/PD model for immediate release zolpidem tablets was constructed in Simcyp®. This model was used to identify the clinically relevant dissolution specifications necessary to ensure efficacy.
Results: According to the simulations, as long as 85% of the drug is released in 45 minutes or less, the impact on the PK and PD profiles of zolpidem would be minimal. According to the FDA, the drug has to dissolve from the test and reference products at a similar rate and to an extent of 85% in not more than 30 minutes to pass bioequivalence via the BCS-biowaiver test. Thus, the BCS-biowaiver specifications are somewhat more stringent than the “safe space” based on the PBPK/PD model. Published data from fasted and fed state pharmacokinetic studies suggest but do not prove a negative food effect of zolpidem.
Conclusions: A PBPK/PD model indicates that current BCS biowaiver criteria are more restrictive for immediate release zolpidem tablets than they need to be. In view of the close relationship between PK and PD, it remains advisable to avoid taking zolpidem tablets with or immediately after a meal, as indicated by the Stilnox® labeling.
Im hymnologischen Bereich sind die Entstehung und jahrhundertelange Tradierung deutscher evangelischer Kirchenlieder von großer Bedeutung. Sie übten in zahlreichen Ländern großen Einfluss aus. Im 19. Jahrhundert beispielsweise wurden sie in das Englische übersetzt und in Ländern dieses Sprachraums gesungen. Bei der Missionierung Koreas wurden westliche – darunter auch einige deutsche – Kirchenlieder eingeführt. Es fällt aber auf, dass im Übertragungsprozess inhaltliche und sprachliche Unterschiede zwischen deutschen und koreanischen Fassungungen auftreten konnten. Auf dieses Geschehen hat die Verfasserin der vorliegenden Studie bei ihrer Tätigkeit als Kirchenmusikerin in Deutschland das Augenmerk gerichtet und es zum Ausgangspunkt ihrer Dissertation gewählt.
Ende des 19. Jahrhunderts wurde Korea von anderen Ländern gezwungen, sich zu öffnen. Daraufhin kamen viele Ausländer – unter ihnen auch christliche Missionare – ins Land, die je eine eigene Gesangbuchliteratur mitbrachten. Insbesondere die amerikanische Mission fasste Fuß. Das erste koreanische Gesangbuch Chanmiga wurde im Jahr 1892 veröffentlicht; ihm folgten weitere Ausgaben. In der ersten Hälfte des 20. Jahrhunderts waren amerikanische Missionare Mitherausgeber dieser Gesangbücher. Folgerichtig dominierte westliches Liedgut.
Die vorliegende Arbeit untersucht jene deutschen Kirchenlieder, die vor 1945 in das Koreanische Gesangbuch aufgenommen wurden. Sie fragt danach, auf welche Weise sie übernommen wurden und sich Änderungen bei ihrer Übermittlung vollzogen haben. Methodisch werden Quellen miteinander verglichen, die zum Zeitpunkt der Aufnahme relevant waren. Dank der älteren deutschen, englischen und amerikanischen Gesangbücher, die online und in deutschen Bibliotheken (Online-Archive) freigeschaltet sowie im Gesangbucharchiv Mainz vorhanden sind, ist diese umfangreiche Forschung möglich geworden.
Die Bedeutung des Singens ist für die koreanische Christenheit während der Annexion durch Japan (1910-1945) groß gewesen. Sie sang als Unabhängigkeitsbewegung Kirchenlieder, unter denen besonders Martin Luthers Choral Ein feste Burg ist unser Gott unverzichtbar wurde. Aussagen zeitgenössischer Christen belegen seine damalige Beliebtheit. Ein Grund dafür liegt darin, dass in ihm zahlreiche Analogien zur Situation der unterdrückten Koreaner erkennbar waren. Das Lied vermittelte ihnen Trost, Mut und einen festen Gottesglauben. Seine besondere Bedeutung erkannte auch das japanische Regime und verbot es während der gesamten Besatzungszeit.
Auch nach 1945 wurden deutsche Kirchenlieder in koreanische Gesangbücher aufgenommen. Ihre Anzahl sank jedoch gegen Ende des 20. Jahrhunderts; das aktuelle Gesangbuch, 21st Century Hymnal, von 2006 enthält nur noch 21. Es ist schließlich festzuhalten, dass Ein feste Burg nicht nur im Gottesdienst, sondern auch im Theater zu hören ist – paradigmatisch in der Oper Son Yang Won, eine Komposition des Kirchenmusikers Chae Hoon Park (*1922) aus dem Jahr 2011. Die Oper trägt den Namen des Märtyrers Yang Won Son (1902-1950) und thematisiert geschichtliche Ereignisse von nationaler Bedeutung: die Problematik der Anarchie, beginnend mit der Landesteilung durch die Sowjetunion und USA in zwei Besatzungszonen 1945 sowie die Yeosu-Sucheon-Rebellion von 1948, organisiert von wenigen kommunistischen Soldaten gegen die südkoreanische Regierung. Die vorliegende Studie untersucht, welche Bedeutung das Lied Ein feste Burg in der Oper einnimmt und wie Chae Hoon Park es bearbeitet hat.
Die Dissertation beschränkt ihre hymnologische Forschung nicht auf die Übernahme und Rezeption deutscher Kirchenlieder in Korea; sie blickt umgekehrt auch auf die Rezeption koreanischer Gesänge in Deutschland. Durch Begegnungen von deutschen mit koreanischen Christen entstanden bzw. entstehen neue Gesänge und Kompositionen und werden durch ökumenische Gottesdienste und Veranstaltungen verbreitet. Die ökumenische Bewegung bewirkte nach dem Zweiten Weltkrieg Änderungen im Liedrepertoire. Gesänge, nicht nur aus England, Europa und Nordamerika, sondern auch aus Afrika, Asien und Südamerika, wurden überall aufgenommen und gesungen. Die aktuellen deutschen und koreanischen Gesangbuchinhalte belegen dies.
Die Ausführungen der Studie halten fest, dass religiöse Bewegungen – Missions- und ökumenische Bewegung – bei der Übermittlung althergebrachter und der Entstehung neuer Lieder eine große Rolle spielten. Dies ist anhand der Entwicklung des Koreanischen Gesangbuchs erkennbar. Früher wurden westliche Kirchenlieder von amerikanischen Missionaren nach Korea transferiert; die einheimischen Christen vernachlässigten wiederum ihre eigene Kultur und Musik. Deshalb dominierte für geraume Zeit westlich geprägtes Liedgut. Die Koreanisierung der Kirchenlieder bzw. Gesangbücher wird nun seit einigen Jahrzehnten forciert. Die wachsende kirchenmusikalische Qualifikation koreanischer Musiker, das zunehmend selbstbewusst werdende einheimische Christentum und die ökumenische Öffnung der Kirchen leisten hier wertvolle Beiträge.
Background: The present study aimed to assess the three‐dimensional changes following soft tissue augmentation using free gingival grafts (FGG) at implant sites over a 3‐month follow‐up period.
Methods: This study included 12 patients exhibiting deficient keratinized tissue (KT) width (i.e., <2 mm) at the vestibular aspect of 19 implants who underwent soft tissue augmentation using FGG at second stage surgery following implant placement. Twelve implants were considered for the statistical analysis (n = 12). The region of interest (ROI) was intraorally scanned before surgery (S0), immediately post‐surgery (S1), 30 (S2) and 90 (S3) days after augmentation. Digital scanned files were used for quantification of FGG surface area (SA) and converted to standard tessellation language (STL) format for superimposition and evaluation of thickness changes between the corresponding time points. FGG shrinkage (%) in terms of SA and thickness was calculated between the assessed time points.
Results: Mean FGG SA amounted to 91 (95% CI: 63 to 119), 76.2 (95% CI: 45 to 106), and 61.3 (95% CI: 41 to 81) mm2 at S1, S2, and S3, respectively. Mean FGG SA shrinkage rate was 16.3% (95% CI: 3 to 29) from S1 to S2 and 33% (95% CI: 19 to 46) from S1 to S3. Mean thickness gain from baseline (S0) to S1, S2, and S3 was 1.31 (95% CI: 1.2 to 1.4), 0.82 (95% CI: 0.5 to 1.12), and 0.37 (0.21 to 0.5) mm, respectively. FGG thickness shrinkage was of 38% (95% CI: 17.6 to 58) from S1 to S2 and 71.8% (95% CI: 60 to 84) from S1 to S3. Dimensional changes from S1 to S3 were statistically significant, P <0.017. Soft tissue healing was uneventful in all patients.
Conclusions: The present three‐dimensional assessment suggests that FGG undergo significant dimensional changes in SA and thickness over a 3‐month healing period.
Objectives: To assess the short‐term clinical outcomes of lateral augmentation of deficient extraction sockets and two‐stage implant placement using autogenous tooth roots (TR).
Material and methods: A total of n = 13 patients (13 implants) were available for the analysis. At the time of tooth extraction, each subject had received lateral augmentation using the respective non‐retainable but non‐infected tooth root where the thickness of the buccal bone was <0.5 mm or where a buccal dehiscence‐type defect was present. Titanium implants were placed after a submerged healing period of 6 months and loaded after 20 ± 2 weeks (V8). Clinical parameters (e.g., bleeding on probing—BOP, probing pocket depth—PD, mucosal recession—MR, clinical attachment level—CAL) were recorded at V8 and after 26 ± 4 weeks (V9) of implant loading.
Results: At V9, all patients investigated revealed non‐significant changes in mean BOP (−19.23 ± 35.32%), PD (0.24 ± 0.49 mm), MR (0.0 ± 0.0 mm) and CAL (0.24 ± 0.49 mm) values, respectively. There was no significant correlation between the initial gain in ridge width and changes in BOP and PD values.
Conclusions: The surgical procedure was associated with stable peri‐implant tissues on the short‐term.
Background: To volumetrically assess the bone microstructure following vertical alveolar ridge augmentation using differently conditioned autogenous tooth roots (TR) and second‐stage implant placement.
Materials and methods: The upper premolars were bilaterally extracted in n = 4 beagle dogs and randomly assigned to either autoclavation (TR‐A) or no additional treatment (TR‐C). Subsequently, TR were used as block grafts for vertical alveolar ridge augmentation in both lower quadrants. At 12 weeks, titanium implants were inserted and left to heal 3 weeks. Microcomputed tomography was used to quantify bone volume per tissue volume (BV/TV), trabecular thickness (Tb.Th), and trabecular spacing (Tb.Sp) at vestibular (v) and oral (o) aspects along the implant and in the augmented upper half of the implant, respectively.
Results: Median BV/TV [TR‐C: 51.33% (v) and 70.42% (o) vs TR‐A: 44.05% (v) and 64.46% (o)], Tb.th [TR‐C: 0.22 mm (v) and 0.27 mm (o) vs TR‐A: 0.23 mm (v) and 0.29 mm (o)] and Tb.Sp [TR‐C: 0.26 mm (v) and 0.13 mm (o) vs TR‐A: 0.29 μm (v) and 0.15 mm (o)] values were comparable in both groups.
Conclusion: Both TR‐C and TR‐A grafts were associated with a comparable bone microstructure within the grafted area.
Der Tumormarker Sialinsäure
(2020)
Die vorliegende Übersicht zum Tumormarker Sialinsäure wird im Rahmen der Serie „Tumormarker“ des Zentralblatts für Arbeitsmedizin, Arbeitsschutz und Ergonomie publiziert, die sich mit dem immer häufigeren Gebrauch der Bestimmung von spezifischen Markern bei sog. Manager-Vorsorgen und Check-up-Untersuchungen beschäftigt. Sialinsäure eignet sich grundsätzlich nicht für solche Vorsorgen, sondern ist ein Marker zur Therapie‑, Verlaufs- und Rezidivkontrolle von Mundhöhlenkarzinomen. Hier zeigt dieser eine hohe Sensitivität und Spezifität, wobei der Marker aber auf keinen Fall als Screeningparameter zur Frühdiagnostik eingesetzt werden soll.
Temperature elevations constitute a major threat to plant performance. In recent years, much was learned about the general molecular mode of heat stress reaction of plants. The current research focuses on the integration of the knowledge into more global networks, including the reactions of cellular compartments. For instance, chloroplast function is central for plant growth and survival, and the performance of chloroplasts is tightly linked to the general status of the cell and vice versa. We examined the changes in photosynthesis, chloroplast morphology and proteomic composition posed in Arabidopsis thaliana chloroplasts after a single or repetitive heat stress treatment over a period of two weeks. We observed that the acclimation is potent in the case of repetitive application of heat stress, while a single stress results in lasting alterations. Moreover, the physiological capacity and its adjustment are dependent on the efficiency of the protein translocation process as judged from the analysis of mutants of the two receptor units of the chloroplast translocon, TOC64, and TOC33. In response to repetitive heat stress, plants without TOC33 accumulate Hsp70 proteins and plants without TOC64 have a higher content of proteins involved in thylakoid structure determination when compared to wild-type plants.
The subfamily Bromelioideae is one of the most diverse groups among the neotropical Bromeliaceae. Previously, key innovations have been identified which account for the extraordinary radiation and species richness of this subfamily, especially in the so-called core Bromelioideae. However, in order to extend our understanding of the evolutionary mechanisms, the genomic mechanisms (e.g. polyploidy, dysploidy) that potentially underlie this accelerated speciation also need to be tested. Here, using PI and DAPI staining and flow cytometry we estimated genome size and GC content of 231 plants covering 30 genera and 165 species and combined it with published data. The evolutionary and ecological significance of all three genomic characters was tested within a previously generated dated phylogenetic framework using ancestral state reconstructions, comparative phylogenetic methods, and multiple regressions with climatic variables. The absolute genome size (2C) of Bromelioideae varied between 0.59 and 4.11 pg, and the GC content ranged between 36.73 and 41.43%. The monoploid genome sizes (Cx) differed significantly between core and early diverging lineages. The occurrence of dysploidy and polyploidy was, with few exceptions, limited to the phylogenetically isolated early diverging tank-less lineages. For Cx and GC content Ornstein–Uhlenbeck models outperformed the Brownian motion models suggesting adaptive potential linked to the temperature conditions. 2C-values revealed different rates of evolution in core and early diverging lineages also related to climatic conditions. Our results suggest that polyploidy is not associated with higher net diversification and fast radiation in core bromelioids. On the other hand, although coupled with higher extinction rates, dysploidy, polyploidy, and resulting genomic reorganizations might have played a role in the survival of the early diverging bromelioids in hot and arid environments.
Reprogramming of tomato leaf metabolome by the activity of heat stress transcription factor HsfB1
(2020)
Plants respond to high temperatures with global changes of the transcriptome, proteome, and metabolome. Heat stress transcription factors (Hsfs) are the core regulators of transcriptome responses as they control the reprogramming of expression of hundreds of genes. The thermotolerance-related function of Hsfs is mainly based on the regulation of many heat shock proteins (HSPs). Instead, the Hsf-dependent reprogramming of metabolic pathways and their contribution to thermotolerance are not well described. In tomato (Solanum lycopersicum), manipulation of HsfB1, either by suppression or overexpression (OE) leads to enhanced thermotolerance and coincides with distinct profile of metabolic routes based on a metabolome profiling of wild-type (WT) and HsfB1 transgenic plants. Leaves of HsfB1 knock-down plants show an accumulation of metabolites with a positive effect on thermotolerance such as the sugars sucrose and glucose and the polyamine putrescine. OE of HsfB1 leads to the accumulation of products of the phenylpropanoid and flavonoid pathways, including several caffeoyl quinic acid isomers. The latter is due to the enhanced transcription of genes coding key enzymes in both pathways, in some cases in both non-stressed and stressed plants. Our results show that beyond the control of the expression of Hsfs and HSPs, HsfB1 has a wider activity range by regulating important metabolic pathways providing an important link between stress response and physiological tomato development.
A growing body of experimental syntactic research has revealed substantial variation in the magnitude of island effects, not only across languages but also across different grammatical constructions. Adopting a well-established experimental design, the present study examines island effects in Spanish using a speeded acceptability judgment task. To quantify variation across grammatical constructions, we tested extraction from four different types of structure (subjects, complex noun phrases, adjuncts and interrogative clauses). The results of Bayesian mixed effects modelling showed that the size of island effects varied between constructions, such that there was clear evidence of subject, adjunct and interrogative island effects, but not of complex noun phrase island effects. We also failed to find evidence that island effects were modulated by participants’ working memory capacity as measured by an operation span task. To account for our results, we suggest that variability in island effects across constructions may be due to the interaction of syntactic, semantic-pragmatic and processing factors, which may affect island types differentially due to their idiosyncratic properties.
Making agriculture sustainable is a global challenge. In the European Union (EU), the Common Agricultural Policy (CAP) is failing with respect to biodiversity, climate, soil, land degradation as well as socio‐economic challenges.
The European Commission's proposal for a CAP post‐2020 provides a scope for enhanced sustainability. However, it also allows Member States to choose low‐ambition implementation pathways. It therefore remains essential to address citizens' demands for sustainable agriculture and rectify systemic weaknesses in the CAP, using the full breadth of available scientific evidence and knowledge.
Concerned about current attempts to dilute the environmental ambition of the future CAP, and the lack of concrete proposals for improving the CAP in the draft of the European Green Deal, we call on the European Parliament, Council and Commission to adopt 10 urgent action points for delivering sustainable food production, biodiversity conservation and climate mitigation.
Knowledge is available to help moving towards evidence‐based, sustainable European agriculture that can benefit people, nature and their joint futures.
The statements made in this article have the broad support of the scientific community, as expressed by above 3,600 signatories to the preprint version of this manuscript. The list can be found here (https://doi.org/10.5281/zenodo.3685632).
A free Plain Language Summary can be found within the Supporting Information of this article.
We study how the Eurosystem Collateral Framework for corporate bonds helps the European Central Bank (ECB) fulfill its policy mandate. Using the ECBs eligibility list, we identify the first inclusion date of both bonds and issuers. We find that due to the increased supply and demand for pledgeable collateral following eligibility, (i) securities lending market trading activity increases, (ii) eligible bonds have lower yields, and (iii) the liquidity of newly-issued bonds declines, whereas the liquidity of older bonds is una↵ected/improves. Corporate bond lending relaxes the constraint of limited collateral supply, thereby making the market more cohesive and complete. Following eligibility, bond-issuing firms reduce bank debt and expand corporate bond issuance, thus increasing overall debt size and extending maturity.
We study how the Eurosystem Collateral Framework for corporate bonds helps the European Central Bank (ECB) fulfill its policy mandate. Using the ECBs eligibility list, we identify the first inclusion date of both bonds and issuers. We find that due to the increased supply and demand for pledgeable collateral following eligibility, (i) securities lending market trading activity increases, (ii) eligible bonds have lower yields, and (iii) the liquidity of newly-issued bonds declines, whereas the liquidity of older bonds is unaffected/improves. Corporate bond lending relaxes the constraint of limited collateral supply, thereby making the market more cohesive and complete. Following eligibility, bond-issuing firms reduce bank debt and expand corporate bond issuance, thus increasing overall debt size and extending maturity.
Market fragmentation and technological advances increasing the speed of trading altered the functioning and stability of global equity limit order markets. Taking market resiliency as an indicator of market quality, we investigate how resilient are trading venues in a high-frequency environment with cross-venue fragmented order flow. Employing a Hawkes process methodology on high-frequency data for FTSE 100 stocks on LSE, a traditional exchange, and on Chi-X, an alternative venue, we find that when liquidity becomes scarce Chi-X is a less resilient venue than LSE with variations existing across stocks and time. In comparison with LSE, Chi-X has more, longer, and severer liquidity shocks. Whereas the vast majority of liquidity droughts on both venues disappear within less than one minute, the recovery is not lasting, as liquidity shocks spiral over the time dimension. Over half of the shocks on both venues are caused by spiralling. Liquidity shocks tend to spiral more on Chi-X than on LSE for large stocks suggesting that the liquidity supply on Chi-X is thinner than on LSE. Finally, a significant amount of liquidity shocks spill over cross-venue providing supporting evidence for the competition for order flow between LSE and Chi-X.
Die vorliegende Arbeit beschäftigt sich mit der außerhäuslichen Alltagsmobilität älterer Menschen, die eine zentrale Schlüsselfunktion in der Erhaltung von Lebensqualität und Gesundheit besonders im höheren Lebensalter einnimmt. Außerhäusliche Alltagsmobilität vollzieht sich stets in einem räumlichen Umweltausschnitt und kann aus ökogerontologischer Perspektive als Ergebnis eines gelungenen Person-Umwelt-Austauschs verstanden werden. Inwiefern psychologische Ressourcen im Sinne mobilitätsspezifischer Einstellungen zum Verständnis von zielgerichteter und habitualisierter Alltagsmobilität älterer Menschen beitragen können, ist Gegenstand der vorliegenden Arbeit. Altersspezifische, mobilitätsrelevante Einstellungen im außerhäuslichen Kontext werden sowohl in der sozialwissenschaftlichen Mobilitäts- und Alternsforschung als auch in der Praxis, etwa im Rahmen einer altersgerechten Stadtgestaltung, bislang noch zu wenig berücksichtigt. Die vorliegende Arbeit reagiert auf dieses Forschungsdesiderat, indem sie mobilitätsspezifische Einstellungen im höheren Lebensalter konzeptuell beschreibt, in den Kontext ökogerontologischer Theorien einbettet und ihre Bedeutung für den Erhalt eines aktiven und gelingenden Alterns untersucht. Im Rahmen der Dissertation wurde zunächst auf der Basis klassischer und neuer ökogerontologischer Modelle das Konstrukt der mobilitätsbezogenen Handlungsflexibilität und Routinen (MBFR) konzeptuell entwickelt. MBFR umfasst einerseits die individuelle Überzeugung, das eigene Mobilitätsverhalten an Herausforderungen außer Haus anpassen zu können (FLEX) und andererseits die Präferenz für mobilitätsbezogene Alltagsroutinen (ROU). Daraufhin wurde ein standardisiertes Messinstrument zur Erfassung des MBFR-Konzepts entwickelt, optimiert und hinsichtlich seiner psychometrischen Qualität untersucht. Die Formulierung der Testitems erfolgte in Anlehnung an bereits existierende Fragebögen zu verwandten Konstrukten. In der vorwiegend online durchgeführten Pilotstudie (Penger & Oswald, 2017) wurden die Items mittels explorativer Faktorenanalysen hinsichtlich ihrer dimensionalen Struktur untersucht. Die Stichprobe umfasste 265 Personen im Alter von 65 Jahren oder älter. Die Analysen des MBFR-Instruments ergaben nach Ausschluss von Items mit niedrigen und nicht eindeutigen Ladungen drei substanzielle Faktoren. Die Items der ersten Dimension bildeten die Überzeugung ab, flexibel mit personenbezogenen, altersassoziierten Herausforderungen (z. B. Schwierigkeiten im Gehen oder auf eine Gehhilfe angewiesen sein) umgehen zu können, um außerhäuslich mobil zu sein. Die Items der zweiten Dimension erfassten die Überzeugung, flexibel mit herausfordernden außerhäuslichen Umweltbedingungen (z. B. eine verlegte Haltestelle oder ein schlechter Zustand der Gehwege) umgehen zu können. Items, die auf den dritten Faktor luden, bildeten die Neigung zu Routinen im Mobilitätsalltag ab, z. B. bekannte Wege beizubehalten oder bei der Ausübung von außerhäuslichen Aktivitäten vertraute Orte aufzusuchen. Während die ersten beiden Faktoren mobilitätsbezogene Handlungsflexibilität (FLEX) messen, werden im dritten Faktor habitualisierte Verhaltensweisen (ROU) erfasst. Alle drei Faktoren wiesen eine akzeptable Reliabilität auf. Auf Basis von Rückmeldungen der Studienteilnehmer:innen wurde das MBFR-Instrument anschließend sprachlich angepasst und gekürzt. Der modifizierte Fragebogen wurde daraufhin in der empirischen Studie „MOBIL bleiben in Stuttgart“ (MBIS) eingesetzt. Dabei sollte die Frage beantwortet werden, ob das finale MBFR-Instrument die zugrundeliegenden Konstrukte valide und reliabel erfasst und die Testwerte somit ausreichende Gültigkeit hinsichtlich faktorieller, Konstrukt- und Kriteriumsvalidität bei älteren Menschen im urbanen Raum aufweisen (Penger & Conrad, eingereicht). Es wurden insgesamt 211 privatwohnende Stuttgarter:innen ab 65 Jahren in persönlichen Interviews und mithilfe eines 7-tägigen Wegetagebuchs zu verschiedenen Aspekten ihrer Mobilität im Wohnumfeld befragt. Statistische Analysen auf latenter Ebene erfolgten mittels Strukturgleichungsmodellen. Bivariate Zusammenhänge und Subgruppenanalysen wurden mittels Korrelations- und Regressionsanalysen berechnet. Die dreifaktorielle Struktur des MBFR-Fragebogens konnte im konfirmatorischen Modell empirisch bestätigt werden. Zudem fiel die interne Konsistenz aller drei Faktoren gut aus. Zusammenhänge zu konstruktverwandten Merkmalen – wie allgemeine und mobilitätsspezifische Einstellungen – deuten darauf hin, dass das MBFR-Instrument ausreichend konvergente Validität aufweist. Analysen auf latenter Ebene ergaben, dass Befragte durchschnittlich mehr außerhäusliche Wege zurückzulegten, wenn sie in stärkerem Maße überzeugt waren, flexibel auf mobilitätsbezogene Herausforderungen reagieren zu können (FLEX). Weiterhin ließen sich positive Zusammenhänge zwischen FLEX und der erlebten Selbstständigkeit sowie dem subjektiven Wohlbefinden aufzeigen. Die Befunde belegen somit hinreichende Übereinstimmungsvalidität der Testwerte. Differenzierte Analysen machten darüber hinaus deutlich, dass FLEX vor allem bei Befragten mit Mobilitätseinschränkungen bedeutsam zur Vorhersage des außerhäuslichen Mobilitätsverhaltens beitrug. ...
Netzwerkmodelle spielen in verschiedenen Wissenschaftsdisziplinen eine wichtige Rolle und dienen unter anderem der Beschreibung realistischer Graphen.
Sie werden häufig als Zufallsgraphen formuliert und stellen somit Wahrscheinlichkeitsverteilungen über Graphen dar.
Meist ist die Verteilung dabei parametrisiert und ergibt sich implizit, etwa über eine randomisierten Konstruktionsvorschrift.
Ein früher Vertreter ist das G(n,p) Modell, welches über allen ungerichteten Graphen mit n Knoten definiert ist und jede Kante unabhängig mit Wahrscheinlichkeit p erzeugt.
Ein aus G(n,p) gezogener Graph hat jedoch kaum strukturelle Ähnlichkeiten zu Graphen, die zumeist in Anwendungen beobachtet werden.
Daher sind populäre Modelle so gestaltet, dass sie mit hinreichend hoher Wahrscheinlichkeit gewünschte topologische Eigenschaften erzeugen.
Beispielsweise ist es ein gängiges Ziel die nur unscharf definierte Klasse der sogenannten komplexen Netzwerke nachzubilden, der etwa viele soziale Netze zugeordnet werden.
Unter anderem verfügen diese Graphen in der Regel über eine Gradverteilung mit schweren Rändern (heavy-tailed), einen kleinen Durchmesser, eine dominierende Zusammenhangskomponente, sowie über überdurchschnittlich dichte Teilbereiche, sogenannte Communities.
Die Einsatzmöglichkeiten von Netzwerkmodellen gehen dabei weit über das ursprüngliche Ziel, beobachtete Effekte zu erklären, hinaus.
Ein gängiger Anwendungsfall besteht darin, Daten systematisch zu produzieren.
Solche Daten ermöglichen oder unterstützen experimentelle Untersuchungen, etwa zur empirischen Verifikation theoretischer Vorhersagen oder zur allgemeinen Bewertung von Algorithmen und Datenstrukturen.
Hierbei ergeben sich insbesondere für große Probleminstanzen Vorteile gegenüber beobachteten Netzen.
So sind massive Eingaben, die auf echten Daten beruhen, oft nicht in ausreichender Menge verfügbar, nur aufwendig zu beschaffen und zu verwalten, unterliegen rechtlichen Beschränkungen, oder sind von unklarer Qualität.
In der vorliegenden Arbeit betrachten wir daher algorithmische Aspekte der Generierung massiver Zufallsgraphen.
Um Anwendern Reproduzierbarkeit mit vorhandenen Studien zu ermöglichen, fokussieren wir uns hierbei zumeist auf getreue Implementierungen etablierter Netzwerkmodelle,
etwa Preferential Attachment-Prozesse, LFR, simple Graphen mit vorgeschriebenen Gradsequenzen, oder Graphen mit hyperbolischer (o.Ä.) Einbettung.
Zu diesem Zweck entwickeln wir praktisch sowie analytisch effiziente Generatoren.
Unsere Algorithmen sind dabei jeweils auf ein geeignetes Maschinenmodell hin optimiert.
Hierzu entwerfen wir etwa klassische sequentielle Generatoren für Registermaschinen, Algorithmen für das External Memory Model, und parallele Ansätze für verteilte oder Shared Memory-Maschinen auf CPUs, GPUs, und anderen Rechenbeschleunigern.
When a visual stimulus is repeated, average neuronal responses typically decrease, yet they might maintain or even increase their impact through increased synchronization. Previous work has found that many repetitions of a grating lead to increasing gamma-band synchronization. Here we show in awake macaque area V1 that both, repetition-related reductions in firing rate and increases in gamma are specific to the repeated stimulus. These effects showed some persistence on the timescale of minutes. Further, gamma increases were specific to the presented stimulus location. Importantly, repetition effects on gamma and on firing rates generalized to natural images. These findings suggest that gamma-band synchronization subserves the adaptive processing of repeated stimulus encounters, both for generating efficient stimulus responses and possibly for memory formation.
Attention selects relevant information regardless of whether it is physically present or internally stored in working memory. Perceptual research has shown that attentional selection of external information is better conceived as rhythmic prioritization than as stable allocation. Here we tested this principle using information processing of internal representations held in working memory. Participants memorized four spatial positions that formed the endpoints of two objects. One of the positions was cued for a delayed match-non-match test. When uncued positions were probed, participants responded faster to uncued positions located on the same object as the cued position than to those located on the other object, revealing object-based attention in working memory. Manipulating the interval between cue and probe at a high temporal resolution revealed that reaction times oscillated at a theta rhythm of 6 Hz. Moreover, oscillations showed an anti-phase relationship between memorized but uncued positions on the same versus other object as the cued position, suggesting that attentional prioritization fluctuated rhythmically in an object-based manner. Our results demonstrate the highly rhythmic nature of attentional selection in working memory. Moreover, the striking similarity between rhythmic attentional selection of mental representations and perceptual information suggests that attentional oscillations are a general mechanism of information processing in human cognition. These findings have important implications for current, attention-based models of working memory.
Aim: To evaluate the level of agreement between the periodontal risk assessment (PRA) and the periodontal risk calculator (PRC).
Materials and methods: Periodontal risk was retrospectively assessed among 50 patients using PRA and PRC. Both methods were modified. PRA by assessing probing pocket depths and bleeding on probing at four (PRA4) and six (PRA6) sites per tooth, PRC by permanently marking or unmarking the dichotomously selectable factors “irregular recall,” “oral hygiene in need of improvement” and “completed scaling and root planing” for PRC. Agreement between PRA and PRCred (summarized risk categories) was determined using weighted kappa.
Results: Fifty patients enrolled in periodontal maintenance (48% female, age: 63.8 ± 11.2 years) participated. PRA4 and PRA6 matched in 32 (64%) patients (κ‐coefficient = 0.48, p < .001). There was 100% agreement between both PRC versions. There was minimal agreement of PRA6 and PRCred (66%, 28% one different category, 6% two different categories; κ‐coefficient = 0.34; p = .001). PRA4 and PRCred did not match (60% agreement, 34% one different category, 6% two different categories; κ‐coefficient = 0.23; p = .13). For the SPT diagnosis of severe periodontitis, PRA6 and PRCred agreed weakly (κ‐coefficient = 0.44; p = .004).
Conclusion: PRA and PRC showed a minimal agreement. Specific disease severity may result in improved agreement.
Background and Objective: Long-term tooth retention is the ultimate goal of periodontal therapy. Aim of this study was to evaluate tooth loss (TL) during 10 years of supportive periodontal therapy (SPT) in periodontal compromised patients and to identify factors influencing TL on patient level. Material and Methods: Patients were re-examined 120 ± 12 months after active periodontal therapy. TL and risk factors [smoking, initial diagnosis, SPT adherence, interleukin-1 polymorphism, cardiovascular diseases, age at baseline, bleeding on probing (BOP), change of practitioner, insurance status, number of SPT, marital and educational status] influencing TL on patient level were assessed. Results: One-hundred patients (52 female, mean age 65.6 ± 11 years) lost 121 of 2428 teeth (1.21 teeth/patient; 0.12 teeth/patient/y) during 10 years of SPT. Forty-two of these were lost for periodontal reasons (0.42 teeth/patient; 0.04 teeth/patient/y). Significantly more teeth were lost due to other reasons (P < .001). Smoking, baseline severity of periodontitis, non-adherent SPT, positive interleukin-1 polymorphism, marital and educational status, private insurance, older age at baseline and BOP, small number of SPT were identified as patient-related risk factors for TL (P < .05). Conclusion: During 120 ± 12 months of SPT, only a small number of teeth was lost in periodontally compromised patients showing the positive effect of a well-established periodontal treatment concept. The remaining risk for TL should be considered using risk-adopted SPT allocation.
Der Beitrag stellt zunächst dar, dass und warum dem geltenden UWG ein schlüssiger innerer Zusammenhang fehlt, und zwar sowohl im Hinblick auf den Prüfungsaufbau für Ansprüche als auch im Hinblick auf die im Gesetz zum Tragen kommenden materiellen Systematisierungskriterien. Sodann wird ein Vorschlag für einen alternativen Gesetzesaufbau unterbreitet, der am unverändert richtigen Gedanken festhält, wonach Wettbewerbsverhalten in seinen komplexen Auswirkungen auf sämtliche Marktteilnehmer ganzheitlich zu erfassen und zu regulieren ist, während die Orientierung an Gruppen von Marktteilnehmern zwangsläufig zu Abgrenzungsproblemen führt. Folglich bilden im unterbreiteten Vorschlag nicht die Schutzsubjekte des UWG, sondern der Unwertgehalt der geschäftlichen Handlung (Irreführung, Aggressivität, sonstige Wettbewerbsverfälschung) das primäre Systematisierungskriterium. Übergeordnetes Ziel des Vorschlags ist es, die methodengerechte Anwendung des geschriebenen Rechts zu erleichtern und auf diese Weise gesetzesferne Eigenrationalitäten der Praxis einzuhegen.
The long-standing battle between economic nationalism and globalism has again taken center stage in geopolitics. This article applies this dichotomy to the law and policy of international intellectual property (IP). Most commentators see IP as a prime example of globalization. The article challenges this view on several levels. In a nutshell, it claims that economic nationalist concerns about domestic industries and economic development lie at the heart of the global IP system. To support this argument, the article summarizes and categorizes IP policies adopted by selected European countries, the European Union, and the U.S. Section I presents three types of inbound IP policies that aim to foster local economic development and innovation. Section II adds three versions of outbound IP policies that, in contrast, target foreign countries and markets. Concluding section III traces a dialectic virtuous circle of economic nationalist motives leading to global legal structures and identifies the function and legal structure of IP as the reason for the resilience and even dominance of economic nationalist motives in international IP politics. IP concerns exclusive private rights that are territorially limited creatures of (supra-)national statutes. These legal structures make up the economic nationalist DNA of IP.
On the basis of the economic theory of network effects, this article provides a novel explanation of the so-called patent paradox, i.e. the question why the propensity to patent is so strong when the expected average value of most patents is low. It demonstrates that the patent system of a country resembles a telephone network or a social media platform. Patents are perceived as nodes in a virtual network that, as a whole, exhibits network effects. It is explained why patents are not independent of other patents but that they complement each other in several ways both within and beyond markets and fields of technology, and that patents thus create synchronization value over and above individual interests of patent holders in exclusivity. As a consequence, the more patents there are, the more valuable it is to also seek patents, and vice versa. Since patents thus display increasing returns to adoption, the willingness to pay for the next patent slopes upwards. This explains why, after a phase of early instability and a certain tipping point, many countries’ patent systems expanded quickly and eventually became a rigid standard (“lock-in”). The concluding section raises the question what regulatory measures are suitable to effectively address the ensuing anticommons effects.
Die rechtshistorische Forschung konzentriert sich auf die Herausbildung spezifisch juristischer Figuren wie das frühneuzeitliche Privileg oder das spätere „geistige Eigentum“. Die Geschichte des urheberrechtlichen Werkbegriffs – immerhin der Gegenstand der „Werkherrschaft“ des Urhebers – hat demgegenüber verhältnismäßig wenig Aufmerksamkeit erfahren. Dabei ist letztlich unstreitig, dass auch die Vorstellung eines von seinen Verkörperungen unabhängigen und daher abstrakt-immateriellen, eigentumsfähigen Werks keine gegebene Wirklichkeit darstellt, sondern erst seit dem Ende des 18. Jahrhunderts etabliert ist. Der Beitrag historisiert das Urheberrecht ausgehend von seiner – so die Hypothese – vorgestellten Wirklichkeit. Betrachtet werden drei Vorbedingungen, die das juristische Reden und Denken in Kategorien eines abstrakt-unkörperlichen, eigentumsfähigen Werks und damit zugleich das „geistige Eigentum“ an diesem Werk möglich gemacht haben: Reproduktionstechnologien, das Ideal des genialen Werks und die dezentral-anonyme Marktwirtschaft.
Das Netzwerkdurchsetzungsgesetz (NetzDG) ist einseitig auf die Löschung rechtswidriger Inhalte ausgerichtet. Vorzugswürdig erscheint demgegenüber ein ganzheitlicher Regulierungsansatz, der darauf abzielt, dass Anbieter großer Universalplattformen gleichermaßen rechtswidrige Inhalte löschen und rechtmäßige Kommunikation nicht willkürlich beeinträchtigen. Dazu wird hier ein konkreter Entwurf zur Änderung des NetzDG nebst Begründung vorgelegt.
Der Beitrag nimmt zu den Entscheidungen des BGH v. 21.2.2019 in Sachen HHole (for Mannheim) u.a., wonach die Vernichtung eines urheberrechtlich geschützten Werks eine „andere Beeinträchtigung“ im Sinne des § 14 UrhG darstellt, kritisch Stellung. Hinterfragt wird insbesondere, worauf sich Entstellungen oder Beeinträchtigungen gem. § 14 UrhG beziehen, was also unter einem „Werk“ gem. § 14 UrhG zu verstehen ist.
Durch die Digitalisierung ist die soziale Bedeutung des Urheberrechts stark gewachsen. Die vom Urheberrecht etablierte Exklusivitätskultur steht überdies in einem fundamentalen Konflikt mit der im Internet vorherrschenden Zugangskultur. Ein Beispiel hierfür ist der Streit um die jüngste Urheberrechtsrichtlinie der EU.
Through digitalization, the social importance of copyright law has grown considerably. Moreover, the culture of exclusivity established by copyright law conflicts fundamentally with the culture of access prevalent on the internet. An example for this is the dispute over the EU’s latest copyright directive. Does it ring in the end of the internet as we know it, or does it »only« see to fair remuneration for those working in the creative economy?
Der Beitrag erläutert aus rechtswissenschaftlicher Sicht, welche Begriffe, Perspektiven und Methoden zur Beantwortung folgender Frage geeignet sind: Wie lässt sich erklären, dass das gerade einmal ca. 200 Jahre alte Rechtsgebiet des „geistigen Eigentums“, dessen Legitimität stets heftig umstritten war, praktisch weltweite Anerkennung in nationalen, supranationalen und völkerrechtlichen Rechtsquellen finden konnte und die globalen Handels- und Kommunikationsströme auch tatsächlich wirksam reguliert? Oder anders gewendet: Wie kann ein schwacher Geltungsanspruch eine faktisch wirkmächtige Ordnung hervorbringen? Nach kritisch-diskurstheoretischen Ansätzen bildet der Streit um Rechtfertigungen den zentralen Treiber normativer Ordnungen. Der Aufsatz zeigt jedoch, dass im Hinblick auf das „geistige Eigentum“ normexterne Bedingungen wie technischer Fortschritt und der Wandel der allgemeinen Wirtschaftsordnung von entscheidender Bedeutung waren und der Frage nach den Gründen z.T. logisch vorausliegen. Schließlich wird gezeigt, dass sozialontologische Analysen besonders gut geeignet erscheinen, strukturelle Normativität/Macht zu adressieren, die unterhalb expliziter Rechtfertigungen bzw. im „Hintergrund“ angesiedelt ist, so wie Sprache generell die logische Voraussetzung für ein rechtfertigendes Rede-und-Antwort-Stehen bildet.
This article documents and classifies instances of transnational intellectual property (IP) enforcement and licensing on the Internet with a particular focus on the territorial reach of the respective regimes. Regarding IP enforcement, I show that the bulk of transnational or even global measures is adopted in the context of “voluntary” self-regulation by various intermediaries, namely domain name registrars, access and host providers, search engines, and advertising and payment services. Global IP licensing is, in contrast, less prevalent than one might expect. It is practically limited to freely accessible Open Content, whereas markets for fee-based services remain territorially fragmented. Overall, three layers of IP governance on the Internet can be distinguished. Based on global licenses, Open Content is freely accessible everywhere. Plain IP infringements are equally combatted on a worldwide scale. Territorial fragmentation persists, instead, in the market segment of fee-based services and in hard cases of conflicts of IP laws/rights. All three universal norms (global accessibility, global illegality, global fragmentation) are supported by a quite solid, “rough” global consensus.
This paper shows that judicial enforcement has substantial effects on firms’ decisions with regard to their employment policies. To establish causality, I exploit a reorganization of the court districts in Italy involving judicial district mergers as a shock to court productivity. I find that an improvement in enforcement, as measured by a reduction in average trial length, has a large, positive effect on firm employment. These effects are stronger in firms with high leverage, or that belong to industries more dependent on external finance and characterized by higher complementarity between labor and capital, consistent with a financing channel driving the results. Moreover, in presence of stronger enforcement, firms can raise more debt to dampen the impact of negative shocks and, in this way, reduce employment fluctuations.
Acinetobacter baumannii is an opportunistic pathogen, which has become a rising threat in healthcare facilities worldwide due to increasing antibiotic resistances and optimal adaptation to clinical environments and the human host. We reported in a former publication on the identification of three phopholipases of the phospholipase D (PLD) superfamily in A. baumannii ATCC 19606T acting in concerted manner as virulence factors in Galleria mellonella infection and lung epithelial cell invasion. This study focussed on the function of the three PLDs. A Δpld1-3 mutant was defect in biosynthesis of the phospholipids cardiolipin (CL) and monolysocardiolipin (MLCL), whereas the deletion of pld2 and pld3 abolished the production of MLCL. Complementation of the Δpld1-3 mutant with pld1 restored CL biosynthesis demonstrating that the PLD1 is implicated in CL biosynthesis. Complementation of the Δpld1-3 mutant with either pld2 or pld3 restored MLCL and CL production leading to the conclusion that PLD2 and PLD3 are implicated in CL and MLCL production. Mutant studies revealed that two catalytic motifs are essential for the PLD3-mediated biosynthesis of CL and MLCL. The Δpld1-3 mutant exhibited a decreased colistin and polymyxin B resistance indicating a role of CL in cationic antimicrobial peptides (CAMPs) resistance.
Der Plexus tympanicus ist ein komplex aufgebautes Nervengeflecht in der Mukosa des Mittelohrs. Aus anatomischen Studien ist bekannt, dass zuführende und wegführende Verbindungen unterschiedlichen Hirnnerven und sympathischen Bahnen angehören. Insbesondere werden parasympathische und sympathische Innervationssysteme beschrieben und damit stellt der Plexus tympanicus einen Plexus des vegetativen Nervensystems dar.
Bisher fehlen detaillierte Analysen über die Chemoarchitektur dieses Plexus. In der vorliegenden Studie soll das Vorhandensein unterschiedlicher Neurotransmitter und -peptide untersucht werden, um Vorstellungen über die Funktion dieses komplexen Geflechts zu entwickeln.
Es wurden immuncytochemische Färbungen an sechs Parallelserien von Kryostatschnitten durchgeführt. Dabei wurden Primärantikörper benutzt, die gegen Cholinacetyltransferase (ChAT), Dopamin-β-Hydroxylase (DBH), Substanz P (SP), Vasoaktives intestinales Peptid (VIP) und Neuropeptid Y (NPY) gerichtet waren. Dadurch konnten sympathische Nervenfasern durch den Nachweis von DBH als Leitenzym für die Noradrenalinsynthese analysiert werden; parasympathische Strukturen konnten durch Anti-ChAT-AK, das Leitenzym für die Acetylcholinsynthese, differenziert werden.
Alle genannten Neurotransmitter und -peptide konnten in den Mittelohrschnitten nachgewiesen werden. Dabei wurden sie in folgenden Lokalisationen gefunden: VIP wurde vor allem in perikapillären Boutons und Gefäßwänden im gesamten Ohrbereich sowie basal im Drüsenbereich des Meatus acusticus externus nachgewiesen. In der Mittelohrschleimhaut war VIP weit verbreitet und gerade im Bereich des Promotoriums waren einzelne Zellen intensiv angefärbt, die Zeichen sekretorischer Aktivität trugen. SP wurde vor allem in netzartigen um Gefäße gelagerten Fasern und in beaded Nervenfasern in der Mittelohrschleimhaut gefunden. Auch im Bereich der Drüsen, vor allem an Talgdrüsen des äußeren Gehörgangs, wurde SP nachgewiesen. NPY-IR zeigte sich in Geflechten um große Gefäße, an motorischen Endplatten der benachbarten Muskulatur, in der Mittelohrschleimhaut, in Nervenstämmen, Ganglien des Mittelohrbereichs und weniger dicht an Drüsen. ChAT-ir Strukturen sind direkt auf dem Knochen aufliegend in der Mittelohrschleimhaut, gefäßbegleitend an motorischen Endplatten und basal an Drüsenzellen vorhanden. ChAT-ir Nervenzellperikaryen wurden in großer Zahl in Ganglien gefunden, außerdem waren die Nerven allgemein leicht positiv. DBH-ir Strukturen wurden zwischen den Drüsen, in den Gefäßwänden der Arterien im Mittelohrbereich und in Nervenstämmen nachgewiesen. Einige DBH-ir Nervenzellperikaryen befanden sich in den Ganglien innerhalb des Mittelohrbereichs und der zuführenden Hirnnerven. Auch in der Mittelohrschleimhaut wurden Perikaryen, teilweise ganglienartig organisiert, gefunden. In verschiedenen Strukturen im Innenohrbereich konnten alle Neurotransmitter und -peptide in unterschiedlich starker Tingierung nachgewiesen werden.
Anhand des Verteilungsmuster lassen sich Kolokalisationen der Neuropeptide mit noradrenergen und cholinergen Neuronen vermuten, die bereits in anderen Studien für verschiedene Komponenten des vegetativen Nervensystems beschrieben wurden. Anhand der vorliegenden Analysen wurden Lokalisationsübereinstimmungen von ChAT und VIP, ChAT und SP und DBH und NPY gefunden.
Diese Studie soll als Grundlage für weitere Untersuchungen dienen. Insbesondere für das Verständnis von Funktionen und Pathologien des Nervengeflechts bedarf es weiterer Forschung. Die vorliegende Arbeit weist eindeutig nach, dass der Plexus tympanicus ein integratives System darstellt, das im Gegensatz zu früheren Vorstellungen einer reinen Durchgangsorganisation alle Voraussetzungen für ein Kontrollsystem erfüllt.
Die Dissertation befasst sich mit Daten zum frühinvasiven kolorektalen Karzinom aus der Westpfalz in einem Zeitraum von 6 Jahren (2010 – 2016). In diesem Zeitraum sind 11% (n=130) frühinvasive kolorektale Karzinome aufgetreten. Davon besitzen 11% (n=14) Lymphknotenmetastasen. Beim pT1 Kolonkarzinom (n=92) treten Lymphknotenmetastasen in 13% (n=12) und beim pT1 Rektumkarzinom (n=38) in 5% (n=2) auf. Zur Risikostratifizierung werden pT1 kolorektale Karzinome in Low-Risk (sm1, G1, G2) und High-Risk (sm3, G3, G4) Karzinome eingeteilt. 84% (n=109) der pT1 kolorektalen Karzinome sind gut (G1) und mäßig differenziert (G2) und 35% (n=46) besitzen eine Submucosaeindringtiefe von sm1. 15% der G1 und G2 (n=11 von 73) pT1 Kolonkarzinome und 6% der G1 und G2 (n=2 von 36) pT1 Rektumkarzinome sind nodal positiv. Ein positiver nodaler Status ist in 12% (n=4 von 33) bei pT1sm1 Kolonkarzinomen aufgetreten. Ähnliches gilt für pT1sm1 Rektumkarzinome mit 8% (n=1 von 13). Weder im sm3 Stadium noch beim G3 pT1 Rektumkarzinom ist ein no-dal positiver Status vorgekommen. Dies zeigt, dass die Einteilung in Low- und High-Risk Karzinome nach der S3–Leitlinie zu überdenken ist. Ein positiver Lymphknoten-status tritt auch bei Low-Risk Karzinomen auf und verschlechtert das onkologische Outcome signifikant. Die Überlebensraten verdeutlichen diese Erkenntnis. Frühinvasi-ve kolorektale Karzinome besitzen eine ähnliche 5 Jahres-Überlebensrate von 81% wie fortgeschrittene neoadjuvant behandelte ypT1 kolorektale Karzinome. Das Gleiche gilt für nodal negative pT1 Karzinome (83%) im Vergleich mit fortgeschrittenen nodal negativen ypT0 und ypT1 Karzinomen (81%). Auch nodal positive pT1 Karzinome und fortgeschrittene nodal positive ypT0 und ypT1 Karzinome haben ähnliche Überle-bensraten (66% versus 67%). Auch dieser Vergleich zeigt, dass frühinvasive kolorekta-le Karzinome unterschätzt werden. Zur Optimierung des onkologischen Outcomes ist eine systemische Therapie bei frühinvasiven kolorektalen Karzinomen - auch ohne Lymphknotenmetastasen - zur Verbesserung des Überlebens nach 5 Jahren zu erwägen. Diese Thematik bietet einen Ansatzpunkt für weitere Studien um eine konkrete Aussa-ge über die Signifikanz einer neo-oder adjuvanten Therapie bei frühinvasiven kolorek-talen Karzinomen zu ermöglichen. Ein angepasstes multimodales Therapiekonzept sowie eine adäquate Nachsorge erscheinen bei frühinvasiven kolorektalen Karzinomen unabdingbar.
Endocannabinoids are important lipid-signaling mediators. Both protective and deleterious effects of endocannabinoids in the cardiovascular system have been reported but the mechanistic basis for these contradicting observations is unclear. We set out to identify anti-inflammatory mechanisms of endocannabinoids in the murine aorta and in human vascular smooth muscle cells (hVSMC). In response to combined stimulation with cytokines, IL-1β and TNFα, the murine aorta released several endocannabinoids, with anandamide (AEA) levels being the most significantly increased. AEA pretreatment had profound effects on cytokine-induced gene expression in hVSMC and murine aorta. As revealed by RNA-Seq analysis, the induction of a subset of 21 inflammatory target genes, including the important cytokine CCL2 was blocked by AEA. This effect was not mediated through AEA-dependent interference of the AP-1 or NF-κB pathways but rather through an epigenetic mechanism. In the presence of AEA, ATAC-Seq analysis and chromatin-immunoprecipitations revealed that CCL2 induction was blocked due to increased levels of H3K27me3 and a decrease of H3K27ac leading to compacted chromatin structure in the CCL2 promoter. These effects were mediated by recruitment of HDAC4 and the nuclear corepressor NCoR1 to the CCL2 promoter. This study therefore establishes a novel anti-inflammatory mechanism for the endogenous endocannabinoid AEA in vascular smooth muscle cells. Furthermore, this work provides a link between endogenous endocannabinoid signaling and epigenetic regulation.
Background: The number of implantable cardioverter defibrillator (ICD) infections is increasing due to an increased number of ICD implants, higher-risk patients, and more frequent replacement procedures, which carry a higher risk of infection. Reducing the morbidity, mortality, and cost of ICD-related infections requires an understanding of the current rate of this complication and its predictors.
Methods: The Shock Implant Evaluation Trial (SIMPLE) trial randomized 2500 ICD recipients to defibrillation testing or not. Over an average of 3.1 years, patients were seen every 6 months and examined for evidence of ICD infection, which was defined as requiring device removal and/or intravenous antibiotics.
Results: Within 24 months, 21 patients (0.8%) developed infection. Fourteen patients (67%) with infection presented within 30 days, 20 patients by 12 months, and only 1 patient beyond 12 months. Univariate analysis demonstrated that patients with primary electrical disorders (3 patients, P = 0.009) and those with a secondary prevention indication (13 patients, P = 0.0009) were more likely to develop infection. Among the 2.2% of patients who developed an ICD wound hematoma, 10.4% developed an infection. Among the 8.3% of patients requiring an ICD reintervention, 1.9% developed an infection.
Conclusions: This cohort of ICD recipients at high-volume centres have a low risk of device-related infection. However; strategies to reduce wound hematoma and the need for ICD reintervention could further reduce the rate of infection.
The risk of increasing dengue (DEN) and chikungunya (CHIK) epidemics impacts 240 million people, health systems, and the economy in the Hindu Kush Himalayan (HKH) region. The aim of this systematic review is to monitor trends in the distribution and spread of DEN/CHIK over time and geographically for future reliable vector and disease control in the HKH region. We conducted a systematic review of the literature on the spatiotemporal distribution of DEN/CHIK in HKH published up to 23 January 2020, following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. In total, we found 61 articles that focused on the spatial and temporal distribution of 72,715 DEN and 2334 CHIK cases in the HKH region from 1951 to 2020. DEN incidence occurs in seven HKH countries, i.e., India, Nepal, Bhutan, Pakistan, Bangladesh, Afghanistan, and Myanmar, and CHIK occurs in four HKH countries, i.e., India, Nepal, Bhutan, and Myanmar, out of eight HKH countries. DEN is highly seasonal and starts with the onset of the monsoon (July in India and June in Nepal) and with the onset of spring (May in Bhutan) and peaks in the postmonsoon season (September to November). This current trend of increasing numbers of both diseases in many countries of the HKH region requires coordination of response efforts to prevent and control the future expansion of those vector-borne diseases to nonendemic areas, across national borders.
Article 4 of Protocol No. 4 to the European Convention on Human Rights (ECHR) is short. Its title reads "Prohibition of collective expulsion of aliens", its text reads: "Collective expulsion of aliens is prohibited." It comes as a historical disappointment that the European Court of Human Rights (ECtHR) in its decision in the case N.D. and N.T. v. Spain from 13 February 2020 distorts this clear guarantee to exclude apparently "unlawful" migrants from its protection. The decision is a shock for the effective protection of rights in Europe and at its external borders. Consequently the Guardian titled that the Court is "under fire". Reading the majority opinion is at times a puzzling experience, to say the least.
Background: Re-treatment in patients with a chronic hepatitis C virus (HCV) infection and a previous failure to direct-acting antiviral (DAA) treatment remains a challenge. Therefore, we investigated the success rate of treatment and re-treatment regimens used at our center from October 2011 to March 2018.
Methods: A retrospective analysis of DAA-based HCV therapies of 1096 patients was conducted. Factors associated with a virological relapse were identified by univariable and multivariable logistic regression, treatment success of the re-treatment regimens was evaluated by an analysis of sustained virological response (SVR) rates in patients with a documented follow-up 12 weeks after the end of treatment.
Results: Of 1096 patients treated with DAA-based regimens, 91 patients (8%) were lost to follow-up, 892 of the remaining 1005 patients (89%) achieved an SVR12. Most patients (65/113, 58%) who experienced a virological relapse received an interferon-based DAA regimen. SVR rates were comparable in special cohorts like liver transplant recipients (53/61, 87%) and people with a human immunodeficiency virus (HIV) coinfection (41/45, 91%). On multivariable analysis, interferon-based DAA therapy was associated with treatment failure (odds ratio 0.111, 95%-confidence interval 0.054–0.218) among others. One hundred seventeen patients with multiple DAA treatment courses were identified, of which 97 patients (83%) experienced a single relapse, but further relapses after two (18/117, 15%) or even three (2/117, 2%) treatment courses were also observed. Eighty-two of 96 (85%) re-treatment attempts with all-oral DAA regimens were successful after an initial treatment failure.
Conclusion: Overall, DAA re-treatments were highly effective in this real-world cohort and only a minority of patients failed more than two treatment courses. Switching to–or addition of–a new drug class seem to be valid options for the re-treatment of patients especially after failure of an interferon-based regimen.
Background: The intraoperative blood loss is estimated daily in the operating room and is mainly done by visual techniques. Due to local standards, the surgical sponge colours can vary (e.g. white in US, green in Germany). The influence of sponge colour on accuracy of estimation has not been in the focus of research yet. Material and methods: A blood loss simulation study containing four “bleeding” scenarios each per sponge colour were created by using expired whole blood donation samples. The blood donations were applied to white and green surgical sponges after dilution with full electrolyte solution. Study participants had to estimate the absorbed blood loss in sponges in all scenarios. The difference to the reference blood loss was analysed. Multivariate linear regression analysis was performed to investigate other influence factors such as staff experience and sponge colour. Results: A total of 53 anaesthesists participated in the study. Visual estimation correlated moderately with reference blood loss in white (Spearman's rho: 0.521; p = 3.748*10−16) and green sponges (Spearman's rho: 0.452; p = 4.683*10−12). The median visually estimated blood loss was higher in white sponges (250ml IRQ 150–412.5ml) than in green sponges (150ml IQR 100-300ml), compared to reference blood loss (103ml IQR 86–162.8). For both colour types of sponges, major under- and overestimation was observed. The multivariate statistics demonstrates that fabric colours have a significant influence on estimation (p = 3.04*10−10), as well as clinician’s qualification level (p = 2.20*10−10, p = 1.54*10−08) and amount of RBL to be estimated (p < 2*10−16). Conclusion: The deviation of correct blood loss estimation was smaller with white surgical sponges compared to green sponges. In general, deviations were so severe for both types of sponges, that it appears to be advisable to refrain from visually estimating blood loss whenever possible and instead to use other techniques such as e.g. colorimetric estimation.
Purpose: Trauma is the leading cause of death in children. In adults, blood transfusion and fluid resuscitation protocols changed resulting in a decrease of morbidity and mortality over the past 2 decades. Here, transfusion and fluid resuscitation practices were analysed in severe injured children in Germany.
Methods: Severely injured children (maximum Abbreviated Injury Scale (AIS) ≥ 3) admitted to a certified trauma-centre (TraumaZentrum DGU®) between 2002 and 2017 and registered at the TraumaRegister DGU® were included and assessed regarding blood transfusion rates and fluid therapy.
Results: 5,118 children (aged 1–15 years) with a mean ISS 22 were analysed. Blood transfusion rates administered until ICU admission decreased from 18% (2002–2005) to 7% (2014–2017). Children who are transfused are increasingly seriously injured. ISS has increased for transfused children aged 1–15 years (2002–2005: mean 27.7–34.4 in 2014–2017). ISS in non-transfused children has decreased in children aged 1–15 years (2002–2005: mean 19.6 to mean 17.6 in 2014–2017). Mean prehospital fluid administration decreased from 980 to 549 ml without affecting hemodynamic instability.
Conclusion: Blood transfusion rates and amount of fluid resuscitation decreased in severe injured children over a 16-year period in Germany. Restrictive blood transfusion and fluid management has become common practice in severe injured children. A prehospital restrictive fluid management strategy in severely injured children is not associated with a worsened hemodynamic state, abnormal coagulation or base excess but leads to higher hemoglobin levels.
Introduction: In recent years, resource-saving handling of allogeneic blood products and a reduction of transfusion rates in adults has been observed. However, comparable published national data for transfusion practices in pediatric patients are currently not available. In this study, the transfusion rates for children and adolescents were analyzed based on data from the Federal Statistical Office of Germany during the past 2 decades. Methods: Data were queried via the database of the Federal Statistical Office (Destasis). The period covered was from 2005 to 2018, and those in the sample group were children and adolescents aged 0–17 years receiving inpatient care. Operation and procedure codes (OPS) for transfusions, procedures, or interventions with increased transfusion risk were queried and evaluated in detail. Results: In Germany, 0.9% of the children and adolescents treated in hospital received a transfusion in 2018. A reduction in transfusion rates from 1.02% (2005) to 0.9% (2018) was observed for the total collective of children and adolescents receiving inpatient care. Increases in transfusion rates were recorded for 1- to 4- (1.41–1.45%) and 5- to 10-year-olds (1.24–1.33%). Children under 1 year of age were most frequently transfused (in 2018, 40.2% of the children were cared for in hospital). Transfusion-associated procedures such as chemotherapy or machine ventilation and respiratory support for newborns and infants are on the rise. Conclusion: Transfusion rates are declining in children and adolescents, but the reasons for increases in transfusion rates in other groups are unclear. Prospective studies to evaluate transfusion rates and triggers in children are urgently needed.
The Brachybasidiaceae are a family of 22 known species of plant-parasitic microfungi belonging to Exobasidiales, Basidiomycota. Within this family, species of the largest genus Kordyana develop balls of basidia on top of stomatal openings. Basidial cells originate from fungal stroma filling substomatal chambers. Species of Kordyana typically infect species of Commelinaceae. During fieldwork in the neotropics, fungi morphologically similar to Kordyana spp. were found on Goeppertia spp. (syn. Calathea spp., Marantaceae), namely on G. panamensis in Panama and on G. propinqua in Bolivia. These specimens are proposed as representatives of a genus new to science, Marantokordyana, based on the distinct host family and molecular sequence data of ITS and LSU rDNA regions. The specimens on the two host species represent two species new to science, M. oberwinkleriana on G. panamensis and M. boliviana on G. propinqua. They differ by the size and shape of their basidia, molecular sequence data of ITS and LSU rDNA regions, and host plant species. In the past, the understanding of Brachybasidiaceae at order and family level was significantly improved by investigation realized by Franz Oberwinkler and his collaborators at the University of Tübingen, Germany. On species level, however, our knowledge is still very poor due to incomplete species descriptions of several existing names in literature, scarceness of specimens, as well as sequence data lacking for many taxa and for further barcode regions. Especially species of Kordyana and species of Dicellomyces are in need of revision.
The paper examines the application of the category of ‘populism’ to Athenian democracy. Unlike previous works on the subject, which have focused on the fifth century, it studies the fourth, where the tradition is much better, since we can refer to contemporary public speeches. It shows that, despite some parallels on the lexical level, 'populist’ strategies matching the criteria of modern political science cannot be identified in Athenian political communication and interprets this result in its historical context.
Nitro fatty acids (NFAs) are endogenously generated lipid mediators deriving from reactions of unsaturated electrophilic fatty acids with reactive nitrogen species. Furthermore, Mediterranean diets can be a source of NFA. These highly electrophilic fatty acids can undergo Michael addition reaction with cysteine residues, leading to post-translational modifications (PTM) of selected regulatory proteins. Such modifications are capable of changing target protein function during cell signaling or in biosynthetic pathways. NFA target proteins include the peroxisome proliferator-activated receptor γ (PPAR-γ), the pro-inflammatory and tumorigenic nuclear factor-κB (NF-κB) signaling pathway, the pro-inflammatory 5-lipoxygenases (5-LO) biosynthesis pathway as well as soluble epoxide hydrolase (sEH), which is essentially involved in the regulation of vascular tone. In several animal models of inflammation and cancer, the therapeutic efficacy of well-tolerated NFA has been demonstrated. This has already led to clinical phase II studies investigating possible therapeutic effects of NFA in subjects with pulmonary arterial hypertension. Albeit Michael acceptors feature a broad spectrum of bioactivity, they have for a rather long time been avoided as drug candidates owing to their presumed unselective reactivity and toxicity. However, targeted covalent modification of regulatory proteins by Michael acceptors became recognized as a promising approach to drug discovery with the recent FDA approvals of the cancer therapeutics, afatanib (2013), ibrutinib (2013), and osimertinib (2015). Furthermore, the Michael acceptor, neratinib, a dual inhibitor of the human epidermal growth factor receptor 2 and epidermal growth factor receptor, was recently approved by the FDA (2017) and by the EMA (2018) for the treatment of breast cancer. Finally, a number of further Michael acceptor drug candidates are currently under clinical investigation for pharmacotherapy of inflammation and cancer. In this review, we focus on the pharmacology of NFA and other Michael acceptor drugs, summarizing their potential as an emerging class of future antiphlogistics and adjuvant in tumor therapeutics.
The cumulant ratios up to fourth order of the Z distributions of the largest fragment in spectator fragmentation following 107,124Sn+Sn and 124La+Sn collisions at 600 MeV/nucleon have been investigated. They are found to exhibit the signatures of a second-order phase transition established with cubic bond percolation and previously observed in the ALADIN experimental data for fragmentation of 197Au projectiles at similar energies. The deduced pseudocritical points are found to be only weakly dependent on the A/Z ratio of the fragmenting spectator source. The same holds for the corresponding chemical freeze-out temperatures of close to 6 MeV.The experimental cumulant distributions are quantitatively reproduced with the Statistical Multifragmentation Model and parameters used to describe the experimental fragment multiplicities, isotope distributions and their correlations with impact-parameter related observables in these reactions. The characteristic coincidence of the zero transition of the skewness with the minimum of the kurtosis excess appears to be a generic property of statistical models and is found to coincide with the maximum of the heat capacity in the canonical thermodynamic fragmentation model.
Erratum for: Cyclic AMP induces transactivation of the receptors for epidermal growth factor and nerve growth factor, thereby modulating activation of MAP kinase, Akt, and neurite outgrowth in PC12 cells.Journal of biological chemistry, 2002 Nov 15;277(46):43623-30. doi: 10.1074/jbc.M203926200. Epub 2002 Sep 5.
Limb stump pain after amputation, due to sensitized neuromas, is a common condition that can cause a great deal of suffering in affected patients. Treatment is difficult, requiring a multidisciplinary approach that is often unsatisfactory. One treatment used to mitigate pain is electrical stimulation (EStim), administered using several different therapeutic approaches. The research described in this dissertation sought to characterize changes in peripheral nerve morphology, and neuroma formation, following limb amputation, with an eye toward developing better treatment strategies, that intervene before neuromas are fully formed. Another focus of this study was to evaluate the effect EStim has on changes in peripheral nerve morphology, and neuroma formation, following limb amputation.
Right forelimbs of 42 male Sprague Dawley rats were amputated. At 3, 7, 28, 60 and 90 days post amputation (DPA) 6 limb stumps, in each group, were harvested and changes in peripheral nerve morphology, and neuroma formation were measured. In addition, limb stumps of 6 EStim treated, 6 sham-treated (deactivated EStim devices), and 6 non-treated rats were harvested at 28 DPA.
Analysis revealed six distinct morphological characteristics of peripheral nerves during nerve regrowth and neuroma development; 1) normal nerve, 2) degenerating axons, 3) axonal sprouts, 4) unorganized bundles of axons in connective tissue, 5) unorganized axon growth into muscles, and 6) unorganized axon growth into fibrotic tissue (neuroma). At the early stages (3 & 7 DPA), normal nerves could be identified throughout the limb stump tissues and small areas of axonal sprouts were present near the distal tip of the stumps. Signs of degenerating axons were evident from 7 to 90 DPA. From day 28 on, variability of nerve characteristics, with signs of unorganized axon growth into muscle and fibrotic tissue, and neuroma formation, became visible in multiple areas of stump tissue. These pathological features became more evident at 60 and 90 DPA. EStim treated stumps revealed neuroma formation in 1 out of 6 animals, whereas in sham and controls, neuroma formation was seen in 4 out of 6 stumps respectively.
We were able to identify 6 separate histological stages of peripheral nerve regrowth and neuroma formation over 90 days following amputation. Axonal regrowth was observed as early as 3 DPA, and signs of unorganized axonal growth and neuroma formation were evident by 28 DPA. Our observations suggest that EStim-based treatment and/or other prevention strategies might be more effective if administered in the initial dynamic stages of neuroma development.
Background: Brodalumab is a fully human monoclonal immunoglobulin IgG2 antibody that binds to the human IL-17 receptor subunit A and by that inhibits the biologic action of IL-17A, IL-17F, IL-17C and IL-17E. Therapy with fumaric acid esters (FAE) is a well established and widely used first-line systemic treatment for subjects with moderate-to-severe plaque psoriasis. Objectives: To compare brodalumab to FAE in terms of clinical efficacy, patient-reported outcomes and safety in subjects with moderate-to-severe plaque psoriasis who were naïve to systemic treatment. Methods: Eligible subjects were randomized 1 : 1 to 210 mg brodalumab injections or oral FAE according to product label in this 24-week, open-label, assessor-blinded, multi-centre, head-to-head phase 4 trial. The primary endpoints were having PASI75 and having sPGA score of 0 or 1 (sPGA 0/1). Subjects with missing values for the primary endpoints were considered non-responders. Results: A total of 210 subjects were randomized. 91/105 subjects completed brodalumab treatment and 58/105 subjects completed FAE treatment. At Week 24, significantly more subjects in the brodalumab group compared to the FAE group had PASI75 (81.0% vs. 38.1%, P < 0.001) and sPGA 0/1 (64.8% vs. 20.0%, P < 0.001). In the brodalumab group, the median time to both PASI75 and to PASI90 was significantly shorter than in the FAE group (4.1 weeks vs. 16.4 weeks, and 7.4 weeks vs. 24.4 weeks, respectively, P < 0.0001 for both). The rate of adverse events was lower in subjects treated with brodalumab compared to subjects treated with FAE (616.4 vs. 1195.8 events per 100 exposure years). No new safety signals were detected for brodalumab. Conclusions: Brodalumab was associated with rapid and significant improvements in signs and symptoms of moderate-to-severe plaque psoriasis, with a superior efficacy profile to what was observed with FAE in systemic-naïve subjects over 24 weeks.
O presente trabalho, de natureza teórica, analisa fragmentos dos escritos de Theodor W. Adorno (1903-1969) e Jean-Paul Sartre (1905-1980) e destaca reflexões para a pesquisa sociológica no campo da Educação, considerando a inflexão que ambos propõem em “direção ao sujeito”. De modo mais específico, realizamos uma leitura de como cada autor refletiu sobre sua própria infância e educação, buscando articular a reflexão autobiográfica que cada um realiza, de diferentes formas, ao núcleo duro de suas concepções teóricas. Ao observarmos como cada autor, na condição de adulto, rememora de forma sistematizada (na filosofia ou na literatura) sua própria infância, refletindo, entre outros aspectos, sobre a condição social de suas famílias e da classe burguesa, a relação com os adultos e com os artefatos (culturais e tecnológicos) de sua época, incluindo a escolarização, podemos também perceber elementos de suas concepções teóricas sobre a subjetividade e de suas análises sobre as vicissitudes do sujeito no contemporâneo. Enquanto que, para Sartre, a infância emerge no âmbito de uma concepção restauradora da narrativa como mediadora da experiência, em um processo, sempre ainda aberto, de transformação da existência, para Adorno, a rememoração sobre sua infância se articula às temáticas da pátria (não como território, mas como humanidade) e da utopia e se coloca como possibilidade de releitura das singularidades das experiências infantis como forma de confrontação e atualização das promessas contidas no passado.
Fokus meiner Doktorarbeit ist die Anwendung und Entwicklung NMR-spektroskopischer Methoden zur Charakterisierung zeitabhängiger Strukturänderungen von Biomolekülen – von lokalen dynamischen Veränderungen bis zur vollständigen Rückfaltung von Proteinen – und fasst die Ergebnisse meiner drei wichtigsten PhD-Projekte zusammen.
In meinem ersten Projekt habe ich die Leistung eines Temperatursprung-Probenkopfs – mit dem Proben mit hoher Salzkonzentration schnell erwärmt werden können – mithilfe einer Hochfrequenzspule technisch optimiert. Die optimierten Radiofrequenz-Bestrahlungsparameter, Lösungsmittel-bedingungen und der reduzierte Arbeitszyklus führten zu einem Temperatursprung von 20 °C in 400 ms. Ich habe eine Cystein-freie Mutante von Barstar hergestellt, die nach Zugabe von Harnstoff bei 0 °C kalt denaturiert werden kann, während sie ihren gefalteten Zustand bei 30 °C hält. Dadurch wurde auch ermöglicht, dass der Rückfaltungsprozess hunderte Male ohne Abbau oder Aggregation wiederholt werden kann. Die Kombination von reversibler Rückfaltung und rascher Temperaturänderung des kalt denaturierten Barstars ermöglichte die Entwicklung eines neuen kinetischen Experiments, bei dem der Rückfaltungsprozess von Barstar mit einem zweidimensionalen Echtzeit-NMR in hoher Zeitauflösung untersucht wird. Die vollständige Rückgratresonanzzuweisung wurde sowohl für den gefalteten als auch für den kalt denaturierten Zustand von Barstar durchgeführt und ergab, dass in der denaturierten Form beide Prolin-Reste einen gemischten Konformationszustand aufweisen. Dabei befindet sich die Tyr47-Pro48-Amidbindung im ungefalteten Zustand hauptsächlich in trans-, während im gefalteten Zustand in der seltenen cis-Konformation. Das neue hochauflösende kinetische Experiment zeigte, dass die Rückfaltung von Barstar durch die trans-cis-Isomerisierung der Tyr47-Pro48-Amidbindung verlangsamt wird, was sowohl die Sekundärstruktur als auch die Bildung der Tertiärstruktur beeinflusst. Basierend auf diesen Ergebnissen konnte ich einen plausiblen Faltungsmechanismus für den langsamen Faltungsweg von kalt denaturiertem Barstar skizzieren. Durch Änderung der Zeitparameter des Heizungszyklus wurde erreicht, dass die Tyr47-Pro48-Amidbindung im ungefalteten Zustand in der cis-Konformation bleibt und daher der schnelle Faltungsweg dominant wird. Das Starten des Magnetisierungstransfers vor der Temperaturänderung ermöglichte die Aufzeichnung eines Spektrums, das den entfalteten Zustand mit dem gefalteten Zustand korreliert. Dieses Spektrum ermöglichte quantitative Analysen des schnellen Faltungsweges und lieferte sogar indirekte Hinweise auf einen Zwischenzustand. Diese Methode aus Kombination von schnellem Temperatursprung und Kaltdenaturierung zeigt ein hohes Potenzial, Proteinfaltung auf atomarer Ebene experimentell zu untersuchen und ein tieferes Verständnis verschiedener Faltungswege zu erlangen.
In meinem zweiten Projekt – das Teil einer interdisziplinären Forschung war – konzentrierte ich mich auf die NMR-spektroskopische Charakterisierung von Nukleinsäuren, die mit einer photolabilen Schutzgruppe modifiziert wurden. Zuerst wurde mithilfe homonuklearer Korrelationsexperimente eine vollständige Protonresonanzzuweisung erreicht. Danach wurde die relative Konfiguration der photolabilen Schutzgruppen bestimmt basierend auf einer dreidimensionalen Modellstruktur und spezifischer NOE-Korrelationen. Des Weiteren wurde ein Strukturmodell unter Verwendung von NOE-Einschränkungen berechnet. Dieses Strukturmodell zeigte eine eingeschränkte Rotation um die CN-Bindung zwischen dem Käfig und der Nukleobase. Das Modell zeigte auch, dass der Käfig in der Hauptrille positioniert ist und nicht in das Lösungsmittel herausklappt. Im Vergleich zu einem zuvor charakterisierten NPE-Käfig führte die erhöhte Größe zu einer weiteren Senkung des Schmelzpunkts, zeigte jedoch einen geringeren Schmelzpunktunterschied zwischen der S- und der R-Konfiguration des Käfigs, wobei die S-Konfiguration zu einer größeren Reduktion des Schmelzpunktes führt. Dieser Trend wurde weiter untersucht und durch ein Screening unterstützt. Durch selektive Wasserinversions-Rückgewinnungsexperimente konnte ich auch zeigen, dass der Käfig die lokale Stabilität nur bis zu einer Entfernung von zwei benachbarten Basenpaaren von der Modifikationsstelle verringert. Die NOE-Daten dienten auch als guter Bezugspunkt, um die Qualität molekulardynamischer Simulationen zu testen, mit denen zusätzliche Käfigdesigns untersucht wurden. Die Kombination aus Synthese, NMR-Spektroskopie und MD-Simulationen ermöglichte bis jetzt die detaillierteste Untersuchung des Effekts vom Einbau eines einzelnen Käfigs zur Destabilisierung der DNA-Sekundärstruktur. Dabei wurden Einschränkungen des möglichen Designs aufgedeckt, aber auch die Entwicklung einer neuen, effizienteren Struktur ermöglicht.
Mein drittes Projekt konzentrierte sich auf die Charakterisierung eines RNA-Modellsystems. NMR-spektroskopische Daten von kleinen RNA-Modellsystemen – wie NOE, skalare Kopplungen, kreuzkorrelierte Relaxationsraten und RDC – sind eine unschätzbare Referenz für MD-Simulationen, obwohl die Menge der verfügbaren Literaturdaten – bis jetzt – sehr begrenzt ist. ...
The C40A/C82A double mutant of barstar has been shown to undergo cold denaturation above the water freezing point. By rapidly applying radio-frequency power to lossy aqueous samples, refolding of barstar from its cold-denatured state can be followed by real-time NMR spectroscopy. Since temperature-induced unfolding and refolding is reversible for this double mutant, multiple cycling can be utilized to obtain 2D real-time NMR data. Barstar contains two proline residues that adopt a mix of cis and trans conformations in the low-temperature-unfolded state, which can potentially induce multiple folding pathways. The high time resolution real-time 2D-NMR measurements reported here show evidence for multiple folding pathways related to proline isomerization, and stable intermediates are populated. By application of advanced heating cycles and state-correlated spectroscopy, an alternative folding pathway circumventing the rate-limiting cis-trans isomerization could be observed. The kinetic data revealed intermediates on both, the slow and the fast folding pathway.
Deconfinement of Mott localized electrons into topological and spin–orbit-coupled Dirac fermions
(2020)
The interplay of electronic correlations, spin–orbit coupling and topology holds promise for the realization of exotic states of quantum matter. Models of strongly interacting electrons on honeycomb lattices have revealed rich phase diagrams featuring unconventional quantum states including chiral superconductivity and correlated quantum spin Hall insulators intertwining with complex magnetic order. Material realizations of these electronic states are, however, scarce or inexistent. In this work, we propose and show that stacking 1T-TaSe2 into bilayers can deconfine electrons from a deep Mott insulating state in the monolayer to a system of correlated Dirac fermions subject to sizable spin–orbit coupling in the bilayer. 1T-TaSe2 develops a Star-of-David charge density wave pattern in each layer. When the Star-of-David centers belonging to two adyacent layers are stacked in a honeycomb pattern, the system realizes a generalized Kane–Mele–Hubbard model in a regime where Dirac semimetallic states are subject to significant Mott–Hubbard interactions and spin–orbit coupling. At charge neutrality, the system is close to a quantum phase transition between a quantum spin Hall and an antiferromagnetic insulator. We identify a perpendicular electric field and the twisting angle as two knobs to control topology and spin–orbit coupling in the system. Their combination can drive it across hitherto unexplored grounds of correlated electron physics, including a quantum tricritical point and an exotic first-order topological phase transition.
Excavation of burrows is an extremely physically demanding activity producing a large amount of metabolic heat. Dissipation of its surplus is crucial to avoid the risk of overheating, but in subterranean mammals it is complicated due to the absence of notable body extremities and high humidity in their burrows. IR-thermography in a previous study on two species of African mole-rats revealed that body heat was dissipated mainly through the ventral body part, which is notably less furred. Here, we analyzed the dorsal and ventral skin morphology, to test if dermal characteristics could contribute to higher heat dissipation through the ventral body part. The thickness of the epidermis and dermis and the presence, extent and connectivity of fat tissue in the dermis were examined using routine histological methods, while vascular density was evaluated using fluorescent dye and confocal microscopy in the giant mole-rat Fukomys mechowii. As in other hitherto studied subterranean mammals, no subcutaneous adipose tissue was found. All examined skin characteristics were very similar for both dorsal and ventral regions: relative content of adipose tissue in the dermis (14.4 ± 3.7% dorsally and 11.0 ± 4.0% ventrally), connectivity of dermal fat (98.5 ± 2.8% and 95.5 ± 6.8%), vascular density (26.5 ± 3.3% and 22.7 ± 2.3%). Absence of large differences in measured characteristics between particular body regions indicates that the thermal windows are determined mainly by the pelage characteristics.
Three AKT serine/threonine kinase isoforms (AKT1/AKT2/AKT3) mediate proliferation, metabolism, differentiation and anti-apoptotic signals. AKT isoforms are activated down- stream of PI3-kinase and also by PI3-kinase independent mechanisms. Mutations in the lipid phosphatase PTEN and PI3-kinase that increase PIP3 levels increase AKT signaling in a large proportion of human cancers. AKT and other AGC kinases possess a regulatory mechanism that relies on a conserved hydrophobic motif (HM) C-terminal to the catalytic core. In AKT, the HM is contiguous to the serine 473 and two other newly discovered (serine 477 and tyrosine 479) regulatory phosphorylation sites. In AKT genes, this regulatory HM region is encoded in the final exon. We identified a splice variant of AKT2 (AKT2-13a), which contains an alternative final exon and lacks the HM regulatory site. We validated the presence of mRNA for this AKT2-13a splice variant in different tissues, and the presence of AKT2-13a protein in extracts from HEK293 cells. When overexpressed in HEK293 cells, AKT2-13a is phosphorylated at the activation loop and at the zipper/turn motif phosphoryla- tion sites but has reduced specific activity. Analysis of the human transcriptome correspond- ing to other AGC kinases revealed that all three AKT isoforms express alternative transcripts lacking the HM regulatory motif, which was not the case for SGK1-3, S6K1-2, and classical, novel and atypical PKC isoforms. The transcripts of splice variants of Akt1-3 excluding the HM regulatory region could lead to expression of deregulated forms of AKT.
Drought is understood as both a lack of water (i.e., a deficit as compared to some requirement) and an anomaly in the condition of one or more components of the hydrological cycle. Most drought indices, however, only consider the anomaly aspect, i.e., how unusual the condition is. In this paper, we present two drought hazard indices that reflect both the deficit and anomaly aspects. The soil moisture deficit anomaly index, SMDAI, is based on the drought severity index, DSI, but is computed in a more straightforward way that does not require the definition of a mapping function. We propose a new indicator of drought hazard for water supply from rivers, the streamflow deficit anomaly index, QDAI, which takes into account the surface water demand of humans and freshwater biota. Both indices are computed and analyzed at the global scale, with a spatial resolution of roughly 50 km, for the period 1981-2010, using monthly time series of variables computed by the global water resources and the model WaterGAP2.2d. We found that the SMDAI and QDAI values are broadly similar to values of purely anomaly-based indices. However, the deficit anomaly indices provide more differentiated, spatial and temporal patterns that help to distinguish the degree of the actual drought hazard to vegetation health or the water supply. QDAI can be made relevant for stakeholders with different perceptions about the importance of ecosystem protection, by adapting the approach for computing the amount of water that is required to remain in the river for the well being of the river ecosystem. Both deficit anomaly indices are well suited for inclusion in local or global drought risk studies.
A plethora of data has highlighted the role of epigenetics in the development of cancer. Initiation and progression of different cancer types are associated with a variety of changes of epigenetic mechanisms, including aberrant DNA methylation, histone modifications, and miRNA expression. At the same time, advances in the available epigenetic tools allow to investigate and reverse these epigenetic changes and form the basis for the development of anticancer drugs in human oncology. Although human and canine cancer shares several common features, only recently that studies emerged investigating the epigenetic landscape in canine cancer and applying epigenetic modulators to canine cancer. This review focuses on the existing studies involving epigenetic changes in different types of canine cancer and the use of small-molecule inhibitors in canine cancer cells.
This thesis reports three experiments on structural choices during grammatical encoding in monolingual adult speakers of German. Conceptual accessibility, one of the most central notions in language production research, as well as the phenomena of structural and perceptual priming are investigated.
In the first two experiments, a manipulation in terms of inherent conceptual accessibility which has shown universal influences on language production - the factor animacy - is combined with a manipulation making the non-canonical passive structure itself more accessible via structural priming.
Results show that, in addition to a preference for animate entities preceding inanimate entities, speakers can be structurally primed. Structural priming of passive structures led to significantly more passive responses compared to (intransitive) baseline structures.
This holds for monologue settings (Experiment 1) as well as dialogue settings (Experiment 2).
The structural priming effect was stronger in the dialogue setting compared to the monologue setting.
The third experiment combines contexts manipulating the derived conceptual accessibility of one of two entities to be described with a visual cueing manipulation increasing the perceptual accessibility of one of the referents.
Whereas a comprehensive literature review as well as the experimental work conducted within this thesis suggest that animacy and topicalization may exert universal influences on structural choices during language production, perceptual accessibility does not seem to have this potential.
In line with previous cross-linguistic work, perceptual priming in form of an implicit visual cueing manipulation did not show significant effects on speakers' structural choices in German.
These findings contrast with findings obtained for English, suggesting that language-specific characteristics in terms of word order flexibility may influence effcts on grammatical encoding during language production.
Increasing the derived accessibility of one of two referents, however, once again showed significant influences on speakers' structural choices with the topicalization of a patient referent leading to an enhanced production of passive responses.
Purpose: The diagnosis of abusive head trauma (AHT) is complex and neuroimaging plays a crucial role. Our goal was to determine whether non-neuroradiologists with standard neuroradiology knowledge perform as well as neuroradiologists with experience in pediatric neuroimaging in interpreting MRI in cases of presumptive AHT (pAHT).
Methods: Twenty children were retrospectively evaluated. Patients had been diagnosed with pAHT (6 patients), non-abusive head trauma-NAHT (5 patients), metabolic diseases (3 patients), and benign enlargement of the subarachnoid spaces (BESS) (6 patients). The MRI was assessed blindly, i.e., no clinical history was given to the 3 non-neuroradiologists and 3 neuroradiologists from 2 different institutions.
Results: Blindly, neuroradiologists demonstrated higher levels of sensitivity and positive predictive value in the diagnosis of pAHT (89%) than non-neuroradiologists (50%). Neuroradiologists chose correctly pAHT as the most probable diagnosis 16 out of 18 times; in contrast, non-neuroradiologists only chose 9 out of 18 times. In our series, the foremost important misdiagnosis for pAHT was NAHT (neuroradiologists twice and non-neuroradiologists 5 times). Only victims of motor vehicle accidents were blindly misdiagnosed as pAHT. No usual household NAHT was not misdiagnosed as pAHT. Neuroradiologists correctly ruled out pAHT in all cases of metabolic diseases and BESS.
Conclusion: MRI in cases of suspected AHT should be evaluated by neuroradiologists with experience in pediatric neuroimaging. Neuroradiologists looked beyond the subdural hemorrhage (SDH) and were more precise in the assessment of pAHT and its differential diagnosis than non-neuroradiologists were. It seems that non-neuroradiologists mainly assess whether or not a pAHT is present depending on the presence or absence of SDH.
Background: Due to the difficulties in the definite diagnosis, data on brain imaging in pediatric patients with central nervous system (CNS)-invasive mold infection (IMD) are scarce. Our aim was to describe brain imaging abnormalities seen in immunocompromised children with CNS-IMD, and to analyze retrospectively whether specific imaging findings and sequences have a prognostic value. Methods: In a retrospective study of 19 pediatric patients with proven or probable CNS-IMD, magnetic resonance imaging (MRI)-findings were described and analyzed. The results were correlated with outcome, namely death, severe sequelae, or no neurological sequelae. Results: 11 children and 8 adolescents (11/8 with proven/probable CNS-IMD) were included. Seven of the patients died and 12/19 children survived (63%): seven without major neurological sequelae and five with major neurological sequelae. Multifocal ring enhancement and diffusion restriction were the most common brain MRI changes. Diffusion restriction was mostly seen at the core of the lesion. No patient with disease limited to one lobe died. Perivascular microbleeding seen on susceptibility weighted imaging (SWI) and/or gradient-echo/T2* images, as well as infarction, were associated with poor prognosis. Conclusions: The presence of infarction was related to poor outcome. As early microbleeding seems to be associated with poor prognosis, we suggest including SWI in routine diagnostic evaluation of immunocompromised children with suspected CNS-IMD.
Background: Patient information materials and decision aids are essential tools for helping patients make informed decisions and share in decision-making. The aim of this study was to investigate the quality of the written patient information materials available at general practices in Styria, Austria.
Methods: We asked general practitioners to send in all patient information materials available in their practices and to answer a short questionnaire. We evaluated the materials using the Ensuring Quality Information for Patients (EQIP-36) instrument.
Results: A total of 387 different patient information materials were available for quality assessment. These materials achieved an average score of 39 out of 100. The score was below 50 for 78% of all materials. There was a significant lack of information on the evidence base of recommendations. Only 9 % of the materials provided full disclosure of their evidence sources. We also found that, despite the poor quality of the materials, 89% of general practitioners regularly make active use of them during consultations with patients.
Conclusion: Based on international standards, the quality of patient information materials available at general practices in Styria is poor. The vast majority of the materials are not suitable as a basis for informed decisions by patients. However, most Styrian general practitioners use written patient information materials on a regular basis in their daily clinical practice. Thus, these materials not only fail to help raise the health literacy of the general population, but may actually undermine efforts to enable patients to make shared informed decisions. To increase health literacy, it is necessary to make high quality, evidence-based and easy-to-understand information material available to patients and the public. For this, it may be necessary to set up a centralized and independent clearinghouse.