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The overall survival for patients with acute lymphoblastic leukemia (ALL) often is the function of age, in particular in 2019 analysis revealed that 5-year overall survival for patients older than 20 years remains below 35% (American Cancer Society, Cancer Facts &Figures 2019). Importantly, one of the major issues in ALL therapy is the ability of tumor cells to escape the treatment via the establishment of an immunosuppressive environment. The tumor microenvironment has gained tremendous importance in the past decade. This is largely based on the reasoning that, in order to devise better therapeutic strategies for patients, we need to gain better understanding into how malignant cells transform their microenvironment to promote growth, escape immune control and gain therapeutic resistance.
TAM receptors (TAMRs) are engaged in innate immune cells as a feed-back mechanism to terminate the immune response and promote the return to homeostasis (Rothlin et al. 2007). In the context of cancers, aberrant TAMR signaling was mainly explored concerning its pro-oncogenic function (Paolino and Penninger 2016). There are only limited data available suggesting the modulation of cancer immune response via TAMR signaling in highly immunogenic solid tumor models (Paolino et al. 2014; Ubil et al. 2018). So far, however, little is known about their potential indirect immune-modulatory function in hematological malignancies. Taking into account the pronounced importance of TAMR signaling in immune cells combined with the leukemic immune tolerance, the current study focused on the function of TAMR and their ligands in anti-leukemic immunity.
This work uncovers the mechanism of dampening anti-leukemic immune response via TAMR signaling on macrophages using the syngeneic BCR-ABL1 B-ALL mouse model. Using genetic depletion of GAS6 in the host environment or ablation of AXL and/or MERTK receptors in macrophages the bone marrow microenvironment could be rewired in order to achieve an efficient anti-leukemic immune response. In particular, the GAS6/AXL blockade triggers an effective NKand T- cell-dependent anti-leukemic response that results in prolonged survival. This finding specifically tackles the obstacle of inefficient bridging between innate and adaptive immune response typical for hematological malignancies in contrast to solid tumors (E. K. Curran, Godfrey, and Kline 2017).
Besides establishing the vital function of TAMR signaling in anti-leukemic immunity using murine models, the analysis of human blood plasma revealed that age-related immune dysregulation was manifested by significant GAS6 decrease and PROS1 upregulation among elderly donors (>60 y.o.) compared to controls (<25 y.o.). These data are indicative that TAMR signaling likely favors the age-dependent immune system decline, which in turn is associated with a poor survival rate of elderly patients diagnosed with leukemia.
In conclusion, using a preclinical ALL model here it was identified in vivo, that Axl significantly increases upon B-ALL challenge in Mph and NK cells. Therefore, AXL targeting, using the orally bioavailable selective inhibitor Bemcentinib, could serve as a powerful approach to revert early immunosuppression created by leukemia.
Taken together these data propose the AXL receptor as a novel immune checkpoint and attractive candidate for the development of a new therapeutic approach via unleashing the patient’s own immune system to combat leukemic cells.
For private investors it is imperative to a) understand and define their own, individual risk preferences, b) assess their financial and demographic circumstances to determine the individual risk-taking potential, and c) form and maintain a well-diversified risky portfolio. The three chapters of my thesis each match one of these three tasks. \\ \noindent The first chapter of my thesis presents novel experimental evidence to test the existence of a potential projection bias in loss aversion, a significant determinant of investor preferences, thus matching task a). The second chapter is devoted to the determination of private investors' risk-taking potential based on their financial and socio-demographic circumstances, matching task b): In a large portfolio experiment, we examine the ability and heterogeneity of lay and professional advisors in matching investor demographics, such as age and income, with risky asset portfolio shares. The third and final chapter addresses the question on how to reach and maintain an efficient risky portfolio, therefore matching task c): It analyzes a decision support system for private investors that allows its users to simulate any arbitrary set of securities, and by reporting aggregated expected return and risk, to optimize their current portfolio.
Autonomous steering of an electric bicycle based on sensor fusion using model predictive control
(2019)
In this thesis a control and steering module for an autonomous bicycle was developed. Based on sensor fusion and model predictive control, the module is able to trace routes autonomously.
The system is developed to run on a Raspberry Pi. An ultrasonic sensor and a 2D Lidar sensor are used for distance measurements. The vehicle’s position is determined by using GPS signals. Additionally, a camera is used to capture pictures for the roadside detection. In order to recognize the road and the position of the vehicle on it, computer vision techniques are used. The captured images are denoised, Canny edge detection is performed and a perspective transformation is applied. Thereafter a sliding window algorithm selects the edges belonging to the roadside and a second order polynomial is fitted to the selected data. Based on this, the road curvature and the lateral position of the vehicle on the road are calculated. The implemented software is thus able to detect straight and curved roads as well as the vehicle’s lateral offset.
A route planning module was implemented to navigate the vehicle from the start to the destination coordinates. This is done by creating an abstract graph of the roads and using Dijkstra’s algorithm to determine the shortest path.
Four MPC controllers were implemented to control the movements of the vehicle. They are based on state space equations derived from the linear single-track vehicle model. This relatively straightforward model makes it possible to predict the vehicle behavior and is efficient to compute. Each controller was built with different parameters for different vehicle speeds to account for the non-linearity of the system. The controllers simulate the future states of the system at each timeslot and select appropriate control signals for steering, throttle and brakes.
In this thesis, all the components of the steering and control module were individually validated. It was established that the each individual component works as expected and certain constraints and accuracy limits were identified. Finally, the closed loop capabilities of the system were assessed using a test vehicle. Despite some limitations imposed by this setup, it was shown that the control module is indeed capable of autonomously navigating a vehicle and avoiding collisions.
This dissertation consists of four self-contained chapters in the overlapping fields of industrial organization and organizational economics on the topics pricing, careers and supervision. Each chapter is the result of an independent research project. The dissertation analyzes empirical research topics by exploring novel observational data sets. It sheds light on open questions in the economic profession by extending fundamental models on pricing in the first two chapters and by challenging conventional explanations and methods on careers and supervision in the last two chapters.
- Chapter 1:
The first chapter is based on joint work with Steffen Eibelshäuser. It models price competition among brick-and-mortar retailers with business hours. Specifically, we propose a dynamic model of intraday price competition featuring spatial differentiation and firm size heterogeneity. The model makes detailed predictions concerning equilibrium-pricing patterns. When spatial differentiation is high and consumers cannot easily switch between retailers, equilibrium prices are stable at oligopoly levels. When differentiation is low, equilibrium prices fluctuate in cycles. The shapes of the cycles depend on the level of differentiation and on retailers’ reaction times. When reaction times decrease, the number of price cycles increases. In a second step, we apply the model to the German retail gasoline market. Gasoline retailers have been using digital price tags for decades and fast-paced price competition with more than ten price changes per day is no exception. Our model has successfully predicted the emergence of an additional intraday subcycle in April 2017. Moreover, we were able to confirm several detailed predictions concerning the shape of equilibrium price paths and individual firm behavior. Finally, we calibrate the model using a generalized method of moments. The model fits the data remarkably well, with coefficients of determination ranging from 60% to 80%. We use the fitted model to evaluate a number of policy counterfactuals. Restricting price increases results in higher prices and decreased welfare, leading us to conclude that regulation of dynamic markets is highly complex and can easily backfire.
- Chapter 2:
The second chapter analyzes the price-matching policies of two gasoline retailers. Customers of these retailers that are able to provide evidence of competitors posting lower prices have the ability to claim price matches. As shown in the first chapter, the Edgeworth Cycle model rationalizes price fluctuations in the German gasoline retail market. To determine policy interactions in cycling markets, this chapter extends the classical Edgeworth Cycle model by price-matching. The model predicts that price-matching retailers post higher prices and initiate price increases. The price-consulted firm anticipates this strategy, posts lower prices, and provokes the implementing firm to restore the price more frequently. Consulted stations also anticipate earlier price restoration reactions from implementing stations and, thus, provoke restorations earlier. This effect dominates in welfare calculations, such that price matching has positive welfare implications.
The second part of the chapter tests the hypotheses with price data on the German gasoline retail market. The estimation exploits a discontinuity in the policy-affected retailers. Therefore, the analysis disentangles the competitive effects of implementing and price-consulted market participants in comparison to retailers that are not affected. As predicted, the posted average and minimum prices of one implementing retailer and its consulted competitors increase. For the other price-matching retailer, I find reduced prices that contradict the model. The last part of the chapter relates the empirics to static models and shows that the dynamic component provides previously undiscovered insights.
- Chapter 3:
The third chapter is based on joint work with Emmanuelle Auriol and Guido Friebel. It represents the subtopic of careers in this dissertation. Specifically, the chapter provides the first comprehensive data collection analysis of women’s careers in all European research institutions in the field of economics. Using a web-scraping algorithm that constantly accesses position information on institutions’ websites, we collect a novel data set on researchers in Europe. These details entail information on researchers’ gender obtained by the first name and a face recognition. Similar to survey data on U.S. institutions, we identify a leaky pipeline, as women are less likely to become professors than men are. The situation is very heterogeneous across Europe. The gap is substantially larger in Western and Southern Europe than in Central and Eastern Europe. Furthermore, we identify institutions with a higher research output and a better research-ranking having a systematically lower share of females in full professor positions as well as entry-level positions for Ph.D. graduates. Austria, Belgium, Italy, Portugal, and Spain are the drivers for this correlation. All these results are in line with the “leaky pipeline” hypothesis, in which, over the different stages of a career, the attrition of women is higher than the one of men. We show that the cohort hypothesis arguing that the lag effect between the time of Ph.D. completion and the time of promotion to a full professorship is unable to explain the current low number of females.
- Chapter 4:
The fourth and last chapter "What does Mystery Shopping do?" is based on joint work with Sidney Block, Guido Friebel, Matthias Heinz, and Nick Zubanov. It addresses an auditing practice with a yearly U.S.-turnover of 19.5 billion USD in 2016 (European Society for Opinion and Market Research, 2017: Global Market Research 2017). The term mystery represents the key aspect of the tool. During an anonymous visit, so-called mystery shoppers perform certain predefined tasks such as purchasing a product, asking questions, registering complaints, or behaving in a certain way. Following their visit, the shoppers provide detailed reports about their experiences to the evaluated firms. The chapter investigates whether the practice is suitable to determine employees’ pay. Contrary to the general understanding that firms are able to observe service quality and, in turn, can proxy for business success with mystery shopping, we do not observe mystery-shopping evaluations to correlate positively with firm performance. A decomposition of the evaluation reports indicates that mystery-shopping scores are biased and the shopper’s identity explains up to 20% of the score’s variance. Thus, the shopper’s identity has the largest impact out of all observable characteristics. With the results that mystery-shopping scores are noisy and biased, we conclude that they are not suitable for performance pay in the context of our study. In addition, we show that if the number of observations is sufficiently large, aggregated scores relate to business success. The required number of shops per evaluation period must be, however, larger by a factor between 3 and 30 per evaluated subject. Hence, cost advantages of mystery shopping diminish such that the cost benefits to customer assessments could vanish completely. The current methodology, however, may still be useful for other employee-related purposes like monitoring, which is in line with the policies of the considered firms.
Droughts impair plant growth, limit global net primary production and are predicted to increase in the course of climate change. Knowledge of the plant drought response on a molecular level can facilitate the selection of drought resistant genotypes and genetic engineering and thereby can help to implement strategies, such as assisted migration projects or crop improvement, in order to preserve natural and agricultural vegetation against droughts.
Studies on gene expression under drought stress were conducted in three species each of the genera Quercus and Panicum, to shed light on the molecular drought response in these species and identify drought responsive genes as a basis for technical applications.
In the genus Quercus, gene expression studies were conducted in the three major European forest trees Q. ilex, Q. pubescens and Q. robur, for which a distributional shift caused by climate change is predicted for the 21st century. RNA-Seq experiments were conducted in the three Quercus species for the first time, ortholog groups were assigned and unregulated genes, as well as drought responsive genes, were identified (Madritsch et al. 2019). For a set of the unregulated genes, a stable expression over the course of long-term drought periods was evaluated in order to enable an application as reference genes for normalizing qRT-PCR experiments (Kotrade 2019a). The reference genes were used in subsequent experiments to generate gene expression profiles over the course of a two-year drought experiment with consecutive drought periods for a set of twelve drought responsive genes and revealed a highly variable gene regulation under long-term drought stress in the Quercus species (Kotrade et al. 2019b).
In the genus Panicum, the gene expression in response to drought was examined in the two wild crop species, P. laetum and P. turgidum, and in the less drought tolerant species P. bisulcatum via RNA-Seq experiments (Kotrade et al. 2020 (in revision). The transcriptomes of the species were sequenced for the first time, ortholog groups were assigned and the gene regulation was compared across the species. The common grounds of the drought response in Panicum were determined by identifying similarities across the species, while the identification of differences between the species led to genes that might contribute to the higher drought tolerance of P. laetum and P. turgidum
A comparison across the two genera showed large differences in the gene regulation upon drought. This might be largely explained by different experimental setups that resulted in different drought conditions in the genera, such as drought intensity, drought duration and velocity of drought development.
The sequence information and the drought responsive genes identified in the Quercus and Panicum species can be used to develop marker assays for marker-assisted selection. The genes that putatively contribute to the higher drought tolerance of the two wild crop Panicum species should be considered as candidate targets in genetic engineering studies. Marker-assisted selection and genetic engineering can be applied, for example, in assisted migration projects to support natural vegetation in the course of climate change or to breed more drought tolerant crop strains to mitigate crop failure rates caused by droughts.
What are the effects of the GDPR on consumer apps? This article presents an analysis of app behavior before and after the regulatory change in data protection in Europe. Based on long-term data collection, we present differences in app permission use and expressed user concerns and discuss their implications. In May 2018, the General Data Protection Regulation (GDPR) changed the data protection obligations of the information industry with the European Union users substantially. One should expect to find changes in code, program behavior and data collection activities. To investigate this expectation, we analyzed data about Android apps request and use of permissions to access sensitive group of data on smartphones, and collected user reviews. Our data shows an overall reduction of both permissions used and of expressed user concern. However, in some areas apps have increased access or user complaints while in addition, many apps carry with them several unused access privileges.
When we browse via WiFi on our laptop or mobile phone, we receive data over a noisy channel. The received message may differ from the one that was sent originally. Luckily it is often possible to reconstruct the original message but it may take a lot of time. That’s because decoding the received message is a complex problem, NP-hard to be exact. As we continue browsing, new information is sent to us in a high frequency. So if lags are to be avoided and as memory is finite, there is not much time left for decoding. Coding theory tackles this problem by creating models of the channels we use to communicate and tailor codes based on the channel properties. A well known family of codes are Low-Density Parity-Check codes (LDPC codes), they are widely used in standards like WiFi and DVB-T2. In practical settings the complexity of decoding a received message can be heavily reduced by using LDPC codes and approximative decoding algorithms. This thesis lays out the basic construction of LDPC codes and a proper decoding using the sum-product algorithm. On this basis a neural network to improve decoding is introduced. Therefore the sum-product algorithm is transformed into a neural network decoder. This approach was first presented by Nachmani et al. and treated in detail by Navneet Agrawal in 2017. To find out how machine learning can improve the codes, the bit error rates of the trained neural network decoder are compared with the bit error rates of the classic sum-product algorithm approach. Experiments with static and dynamic training datasets of diverse sizes, various signal-to-noise ratios, a feed forward as well as a recurrent architecture show how to tune the neural network decoder even further. Results of the experiments are used to verify statements made in Agrawal’s work. In addition, corrections and improvements in the area of metrics are presented. An implementation of the neural network to facilitate access for others will be made available to the public.
Humans accumulate knowledge throughout their entire lives. In what ways does this accumulation of knowledge influence learning of new information? Are there age-related differences in the way prior knowledge is leveraged for remembering new information? We review studies that have investigated these questions, focusing on those that have used the memory congruency effect, which provides a quantitative measure of memory advantage because of prior knowledge. Regarding the first question, evidence suggests that the accumulation of knowledge is a key factor promoting the development of memory across childhood and counteracting some of the decline in older age. Regarding the second question, evidence suggests that, if available knowledge is controlled for, age-related differences in the memory congruency effect largely disappear. These results point to an age-invariance in the way prior knowledge is leveraged for learning new information. Research on neural mechanisms and implications for application are discussed.
A massive occurrence of microbial carbonates, including abundant sponge remains, within the Devonian Elbingerode Reef Complex was likely deposited in a former cavity of the fore-reef slope during the early Frasnian. It is suggested that the formation of microbial carbonate was to a large part favored by the activity of heterotrophic, i.e., sulfate-reducing bacteria, in analogy to Quaternary coral reef microbialites. The Elbingerode Reef Complex is an example of an oceanic or Darwinian barrier reef system. In modern barrier reef settings, microbialite formation is commonly further facilitated by weathering products from the central volcanic islands. The Devonian microbialites of the Elbingerode Reef Complex occur in the form of reticulate and laminated frameworks. Reticulate framework is rich in hexactinellid glass sponges, the tissue decay of which led to the formation of abundant micrite as well as peloidal and stromatactis textures. Supposed calcimicrobes such as Angusticellularia (formerly Angulocellularia) and Frutexites, also known from cryptic habitats, were part of the microbial association. The microbial degradation of sponge tissue likely also contributed to the laminated framework accretion as evidenced by the occurrence of remains of so-called “keratose” demosponges. Further typical textures in the microbialite of the Elbingerode Reef Complex include zebra limestone, i.e., the more or less regular intercalation of microbial carbonate and cement. Elevated concentrations of magnesium in the microbialite as compared to the surrounding metazoan (stromatoporoid-coral) reef limestone suggests that the microbialite of the Elbingerode Reef Complex was initially rich in high-magnesium calcite, which would be yet another parallel to modern, cryptic coral reef microbial carbonates. Deposition and accretion of the microbialite largely occurred in oxygenated seawater with suboxic episodes as indicated by the trace element (REE + Y) data.
The sum of Lyapunov exponents Lf of a semi-stable fibration is the ratio of the degree of the Hodge bundle by the Euler characteristic of the base. This ratio is bounded from above by the Arakelov inequality. Sheng-Li Tan showed that for fiber genus g≥2 the Arakelov equality is never attained. We investigate whether there are sequences of fibrations approaching asymptotically the Arakelov bound. The answer turns out to be no, if the fibration is smooth, or non-hyperelliptic, or has a small base genus. Moreover, we construct examples of semi-stable fibrations showing that Teichmüller curves are not attaining the maximal possible value of Lf.
Purpose: To compare Cancer-specific mortality (CSM) in patients with Squamous cell carcinoma (SCC) vs. non-SCC penile cancer, since survival outcomes may differ between histological subtypes. Methods: Within the Surveillance, Epidemiology and End Results database (2004–2016), penile cancer patients of all stages were identified. Temporal trend analyses, cumulative incidence and Kaplan–Meier plots, multivariable Cox regression and Fine and Gray competing-risks regression analyses tested for CSM differences between non-SCC vs. SCC penile cancer patients. Results: Of 4,120 eligible penile cancer patients, 123 (3%) harbored non-SCC vs. 4,027 (97%) SCC. Of all non-SCC patients, 51 (41%) harbored melanomas, 42 (34%) basal cell carcinomas, 10 (8%) adenocarcinomas, eight (6.5%) skin appendage malignancies, six (5%) epithelial cell neoplasms, two (1.5%) neuroendocrine tumors, two (1.5%) lymphomas, two (1.5%) sarcomas. Stage at presentation differed between non-SCC vs. SCC. In temporal trend analyses, non-SCC diagnoses neither decreased nor increased over time (p > 0.05). After stratification according to localized, locally advanced, and metastatic stage, no CSM differences were observed between non-SCC vs. SCC, with 5-year survival rates of 11 vs 11% (p = 0.9) for localized, 33 vs. 37% (p = 0.4) for locally advanced, and 1-year survival rates of 37 vs. 53% (p = 0.9) for metastatic penile cancer, respectively. After propensity score matching for patient and tumor characteristics and additional multivariable adjustment, no CSM differences between non-SCC vs. SCC were observed. Conclusion: Non-SCC penile cancer is rare. Although exceptions exist, on average, non-SCC penile cancer has comparable CSM as SCC penile cancer patients, after stratification for localized, locally invasive, and metastatic disease.
In partially molten regions inside the earth melt buoyancy may trigger upwelling of both solid and fluid phases, i.e. diapirism. If the melt is allowed to move separately with respect to the matrix, melt perturbations may evolve into solitary porosity waves. While diapirs may form on a wide range of scales, porosity waves are restricted to sizes of a few times the compaction length. Thus, the size of a partially molten perturbation controls whether a diapir or a porosity wave will emerge. We study the transition from diapiric rise to solitary porosity waves by solving the two-phase flow equations of conservation of mass and momentum in 2D with porosity dependent matrix viscosity. We systematically vary the initial size of a porosity perturbation from 1 to 100 times the compaction length. If the perturbation is much larger than a regular solitary wave, its Stokes velocity is large and therefore faster than the segregating melt. Consequently, the fluid is not able to form a porosity wave and a diapir emerges. For small perturbations solitary waves emerge, either with a positive or negative vertical matrix velocity inside. In between the diapir and solitary wave regimes we observe a third regime of solitary wave induced focusing of melt. In these cases, diapirism is dominant but the fluid is still fast enough to locally build up small solitary waves which rise slightly faster than the diapir and form finger like structures at the front of the diapir. In our numerical simulations the width of these fingers is controlled by the compaction length or the grid size, whichever is larger. In cases where the compaction length becomes similar to or smaller than the grid size the finger-like leading solitary porosity waves are no more properly resolved, and too big and too fast waves may be the result. Therefore, one should be careful in large scale two-phase flow modelling with melt focusing especially when compaction length and grid size are of similar order.
The analysis of charcoal fragments in peat and lake sediments is the most widely used approach to reconstruct past biomass burning. With a few exceptions, this method typically relies on the quantification of the total charcoal content of the sediment. To enhance charcoal analyses for the reconstruction of past fire regimes, and to make the method more relevant to studies of both plant evolution and fire management, more information must be extracted from charcoal particles. Here, I burned in the laboratory seven fuel types comprising 17 species from boreal Siberia, and build on published schemes to develop morphometric and finer diagnostic classifications of the experimentally charred particles. As most of the species used in this study are common to Northern Hemisphere forests and peatlands, these results can be directly applicable over a broad geographical scale. Results show that the effect of temperature on charcoal production is fuel dependent. Graminoids and Sphagnum, and wood (trunk) lose the most mass at low burn temperatures, whereas heathland shrub leaves, brown moss, and ferns retain the most mass at high burn temperatures. In contrast to the wood of trunk, the wood of twigs retained their mass at intermediate temperature. This suggests that species with low mass retention at hotter burning temperatures might be underrepresented in the fossil charcoal record. Charred particle aspect ratio (L/W) appeared to be the strongest indicator of the fuel type burnt. Graminoid charcoals are more elongate than those of all other fuel types, leaf charcoals are the shortest and bulkiest, and twig and wood charcoals are intermediate. Finer diagnostic features were the most useful in distinguishing between wood, graminoid, and leaf particles, but further distinctions within these fuel types are difficult. High-aspect-ratio particles dominated by graminoid and Sphagnum morphologies are robust indicators of cooler surface fires. Contrastingly, abundant wood and leaf morphologies and low-aspect-ratio particles likely indicate higher-temperature fires. However, the overlapping morphologies of leaves and wood from trees and shrubs make it hard to distinguish between high-intensity surface fires combusting living shrubs and dead wood and leaves or high-intensity crown fires combusting living trees. Despite these limitations, the combined use of charred-particle aspect ratios and fuel morphotypes can aid in more robustly interpreting changes in fuel source and fire type, thereby substantially refining histories of past wildfires. Further fields of investigation to improve the interpretation of the fossil charcoal records will require: i) More in-depth knowledge of plant anatomy for a better determination of fuel sources; ii) Relate the proportion of particular charcoal morphotypes to the quantity of biomass; iii) Link the chemical composition of fuels, combustion temperature, and charcoal production. The advanced use of image-recognition software to collect data on other charcoal features could also aid in extracting fire temperatures as well as a change in particles morphology and morphometry during particles transportation.
In the last decade, the Climate Limited-area Modeling (CLM) Community has contributed to the Coordinated Regional Climate Downscaling Experiment (CORDEX) with an extensive set of regional climate simulations. Using several versions of the COSMO-CLM community model, ERA-Interim reanalysis and eight Global Climate Models from phase 5 of the Coupled Model Intercomparison Project (CMIP5) were dynamically downscaled with horizontal grid spacings of 0.44◦(∼50 km), 0.22◦ (∼25 km) and 0.11◦ (∼12 km) over the CORDEX domains Europe, South Asia, East Asia, Australasia and Africa. This major effort resulted in 80 regional climate simulations publicly available through the Earth System Grid Federation (ESGF) web portals for use in impact studies and climate scenario assessments. Here we review the production of these simulations and assess their results in terms of mean near-surface temperature and precipitation to aid the future design of the COSMO-CLM model simulations. It is found that a domain-specific parameter tuning is beneficial, while increasing horizontal model resolution (from 50 to 25 or 12 km grid spacing) alone does not always improve the performance of the simulation. Moreover, the COSMO-CLM performance depends on the driving data. This is generally more important than the dependence on horizontal resolution, model version and configuration. Our results emphasize the importance of performing regional climate projections in a coordinated way, where guidance from both the global (GCM) and regional (RCM) climate modelling communities is needed to increase the reliability of the GCM-RCM modelling chain.
In this study, we determine spectral characteristics and amplitude decays of wind turbine induced seismic signals in the far field of a wind farm (WF) close to Uettingen/Germany. Average power spectral densities (PSD) are calculated from 10 min time segments extracted from (up to) 6-months of continuous recordings at 19 seismic stations, positioned along an 8 km profile starting from the WF. We identify 7 distinct PSD peaks in the frequency range between 1 Hz and 8 Hz that can be observed to at least 4 km distance; lower-frequency peaks are detectable up to the end of the profile. At distances between 300 m and 4 km the PSD amplitude decay can be described by a power law with exponent b. The measured b-values exhibit a linear frequency dependence and range from b = 0.39 at 1.14 Hz to b = 3.93 at 7.6 Hz. In a second step, the seismic radiation and amplitude decays are modeled using an analytical approach which approximates the surface-wave field. Since we observe temporally varying phase differences between seismograms recorded directly at the base of the individual wind turbines (WTs), source-signal phase information is included in the modeling approach. We show that phase differences between source signals have significant effects on the seismic radiation pattern and amplitude decays. Therefore, we develop a phase-shift-elimination-method to handle the challenge of choosing representative source characteristics as an input for the modeling. To optimize the fitting of modeled and observed amplitude decay curves, we perform a grid search to constrain the two model parameters, i.e., the seismic shear wave velocity and quality factor. The comparison of modeled and observed amplitude decays for the 7 prominent frequencies shows very good agreement and allows to constrain shear velocities and quality factors for a two-layer model of the subsurface. The approach is generalized to predict amplitude decays and radiation patterns for WFs of arbitrary geometry.
Hyrrokkin sarcophaga is a parasitic foraminifer that is commonly found in cold-water coral reefs where it infests the file clam Acesta excavata and the scleractinian coral Lophelia pertusa. Here, we present measurements of the elemental and isotopic composition of this parasitic foraminifer for the first time, analyzed by inductively coupled optical emission spectrometry (ICP-OES), electron probe micro analysis (EPMA) and mass spectrometry (MS). Our results reveal that the geochemical signature of H. sarcophaga depends on the host organism it infests. Sr/Ca ratios are 1.1 mmol mol-1 higher in H. sarcophaga that infest L. pertusa, which could be an indication that dissolved host carbonate material is utilised in shell calcification, given that the aragonite of L. pertusa has a naturally higher Sr concentration compared to the calcite of A. excavata.Similarly, we measure 3.1 ‰ lower δ13C and 0.25 ‰ lower δ18O values in H. sarcophaga that lived on20 L. pertusa, which might be caused by the direct uptake of the host’s carbonate material with a more negative isotopic composition or different pH regimes in these foraminifera (pH can exert a control on the extent of CO2 hydration/hydroxylation) due to the uptake of body fluids of the host. We also observe higher Mn/Ca ratios in foraminifers that lived on A. excavata but did not penetrate the host shell compared to specimen that penetrated the shell, which could be interpreted as a change in food source, changes in the calcification rate, Rayleigh fractionation or changing oxygen conditions. While our measurements provide an interesting insight into the calcification process of this unusual foraminifer, these data also indicate that the geochemistry of this parasitic foraminifer is unlikely to be a reliable indicator of paleoenvironmental conditions using Sr/Ca, Mn/Ca, δ18O or δ13C unless the host organism is known and its geochemical composition can be accounted for.
National Greenhouse Gas Inventories (GHGI) are submitted annually to the United Nations Framework Convention on Climate Change (UNFCCC). They are estimated in compliance with Intergovernmental Panel on Climate Change (IPCC) methodological guidance using activity data, emission factors and facility-level measurements. For some sources, the outputs from these calculations are very uncertain. Inverse modelling techniques that use high-quality, long-term measurements of atmospheric gases have been developed to provide independent verification of national GHGI. This is considered good practice by the IPCC as it helps national inventory compilers to verify reported emissions and to reduce emission uncertainty. Emission estimates from the InTEM (Inversion Technique for Emissions Modelling) model are presented for the UK for the hydrofluorocarbons (HFCs) reported to the UNFCCC (HFC-125, HFC-134a, HFC-143a, HFC-152a, HFC-23, HFC-32, HFC-227ea, HFC-245fa, HFC-43-10mee and HFC-365mfc). These HFCs have high Global Warming Potentials (GWPs) and the global background mole fractions of all but two are increasing, thus highlighting their relevance to the climate and a need for increasing the accuracy of emission estimation for regulatory purposes. This study presents evidence that the long-term annual increase in growth of HFC-134a has stopped and is now decreasing. For HFC-32 there is an early indication its rapid global growth period has ended, and there is evidence that the annual increase in global growth for HFC-125 has slowed from 2018. The inverse modelling results indicate that the UK implementation of European Union regulation of HFC emissions has been successful in initiating a decline in UK emissions in the since 2018. Comparison of the total InTEM UK HFC emissions in 2020 with the average from 2009–2012 shows a drop of 35%, indicating progress toward the target of a 79% decrease in sales by 2030. The total InTEM HFC emission estimates (2008–2018) are on average 73 (62–83)% of, or 4.3 (2.7–5.9) Tg CO2-eq yr−1 lower than, the total HFC emission estimates from the UK GHGI inventory. There are also significant discrepancies between the two estimates for the individual HFCs.
Background: Patients with colorectal carcinoma and high-grade microsatellite instability (MSI-H) or deficiency in mismatch repair (dMMR) exceptionally respond to immune checkpoint inhibitors (ICIs). ICIs are more active in treatment-naïve patients than in patients with refractory MSI-H/dMMR metastatic colorectal cancer and even more active in patients with locally advanced tumors. Material and Methods: A 33-year-old male patient with Lynch syndrome was diagnosed with a locally advanced rectal cancer and refused standard neoadjuvant chemoradiation because of the potential harm of sexual dysfunction. MMR and microsatellite instability status were analyzed by immunohistochemistry and fragment length polymerase chain reaction followed by capillary electrophoresis. Results: After MSI-H/dMMR was confirmed, the patient was treated with ICIs (1 mg/kg ipilimumab at day 1 and 3 mg/kg nivolumab at day 1 and 15). A complete clinical response was documented at day 21 after start of treatment. The patient underwent a total mesorectal excision at day 30. In the extirpated tissue, a complete pathological response was confirmed. Conclusion: In MSI-H/dMMR locally advanced rectal cancer short-course ICI treatment is highly effective and may be discussed in patients with dMMR locally advanced rectal cancer.
From age 5 to 7, there are remarkable improvements in children’s cognitive abilities (“5–7 shift”). In many countries, including Germany, formal schooling begins in this age range. It is, thus, unclear to what extent exposure to formal schooling contributes to the “5–7 shift.” In this longitudinal study, we investigated if schooling acts as a catalyst of maturation. We tested 5-year-old children who were born close to the official cutoff date for school entry and who were still attending a play-oriented kindergarten. One year later, the children were tested again. Some of the children had experienced their first year of schooling whereas the others had remained in kindergarten. Using 2 functional magnetic resonance imaging tasks that assessed episodic memory formation (i.e., subsequent memory effect), we found that children relied strongly on the medial temporal lobe (MTL) at both time points but not on the prefrontal cortex (PFC). In contrast, older children and adults typically show subsequent memory effects in both MTL and PFC. Both children groups improved in their memory performance, but there were no longitudinal changes nor group differences in neural activation. We conclude that successful memory formation in this age group relies more heavily on the MTL than in older age groups.
T-cell development is a highly dynamic and stepwise process comprimising T lineage commitment, T-cell receptor (TCR) gene rearrangements and subsequent selection. From a quantitative point of view, only a few hundred progenitor cells migrate from the bone marrow into the thymus. Developing thymocytes (termed double negative (DN), CD4-CD8-) can be further divided into DN1-4 cells based on the expression of CD25 and CD44. These developmental events are interspersed by proliferative bursts which ultimately lead to the generation of millions of double positive (DP, CD4+CD8+) thymocytes that then undergo selection. As a consequence, a proportion of naïve T-cells evolves to ensure adaptive, but not autoreactive immunity.
Previous studies of our lab focused on the quantification of thymus colonization and identified thymus entry to be dependent on expression of the chemokine receptors CCR7 and CCR9 (Krueger et al., 2010; Ziętara et al., 2015). CCR7/9 double knockout (DKO) mice are almost completely devoid of the most immature thymocyte populations (DN1 and DN2), but show near normal DN3 cellularity. Interestingly, a similar defect during early development but a virtually complete recovery of later stages and total thymocyte numbers was also observed in thymi of miR-17~92 deficient mice. Here, a failure of prethymic IL-7 signaling dampens early T-cell development (Regelin et al., 2015). For this reason, we hypothesized a tight regulation of thymocyte population size through alterations in the underlying cell cycle kinetics.
In this thesis, we employed in vivo single- and dual-nucleoside pulse labeling combined with determination of DNA replication over time in different WT thymocyte subsets at steady-state. Based on this, we assessed alterations in cell cycle kinetics of CCR7/9 and miR-17~92 defcicient mice and identified compensatory mechanisms of thymocytes on the level of cell cycle phase distribution and cell cycle speed. In addition, single-cell RNA sequencing helped to obtain information on cell cycle dynamics of early thymocyte subsets, exemplarily shown for WT and CCR7/9 DKO mice. Lastly, we performed cell cycle analyses in a model of endogenous thymic repair upon sublethal total body irradiation which provided insight into intrathymic cell cycle regulation as an adjustable system to re-establish normal thymus cellularity.
In the second part of the thesis, we addressed the role of miR-21 in the thymus. In various studies, we and others identified miRNAs as key posttranscriptional regulators of the immune system and especially for T-cell development (Regelin et al. 2015; Mildner et al. 2017; Li et al. 2007; Ebert et al. 2009; Ziętara et al. 2013; Schaffert et al. 2015). The dynamic expression of miR-21 during T-cell development (Neilson et al. 2007; Kirigin et al. 2012; Kuchen et al. 2010) prompted us to hypothesize that miR-21 has a regulatory function in the thymus. A miR 21-knockout mouse model allowed us to study the role of this miRNA for the development of T-cells in the thymus and the maintenance of T-cells in the periphery. In addition, we performed competitive bone marrow chimera experiments in the context of miR-21 deficiency and overexpression. Further insights were provided by exploring the function of miR-21 in negative selection in vivo as well as in T-cell differentiation in coculture experiments in vitro. To unravel implications of miR-21 to regulate cellular stress responses, we assessed the contribution of miR-21 in a model of endogenous regeneration of the thymus after sublethal irradiation. We could not provide evidence for a prominent role for miR-21 during T-cell development. Together, our experiments revealed that miR-21 is largely dispensable for physiologic T-cell development despite high and dynamic expression in the thymus (Kunze Schumacher et al., 2018). The apparent discrepancy between dynamic expression but lack of a regulatory function in the thymus led us to conclude that miR-21 is rather fine tuning T-cell responses than controlling a developmental event.
Mosquito breeding sites are complex aquatic environments with wide microbial diversity and physicochemical parameters that can change over time during the development of immature insect stages. Changes in biotic and abiotic conditions in water can alter life-history traits of adult mosquitos but this area remains understudied. Here, using microbial genomic and metabolomics analyses, we explored the metabolites associated with Aedes aegypti breeding sites as well as the potential contribution of Klebsiella sp., symbiotic bacteria highly associated with mosquitoes. We sought to address whether breeding sites have a signature metabolic profile and understand the metabolite contribution of the bacteria in the aquatic niches where Ae. aegypti larvae develop. An analysis of 32 mosquito-associated bacterial genomes, including Klebsiella, allowed us to identify gene clusters involved in primary metabolic pathways. From them, we inferred metabolites that could impact larval development (e.g., spermidine), as well as influence the quality assessment of a breeding site by a gravid female (e.g., putrescine), if produced by bacteria in the water. We also detected significant variance in metabolite presence profiles between water samples representing a decoupled oviposition event (oviposition by single females and manually deposited eggs) versus a control where no mosquito interactions occurred (PERMANOVA: p < 0.05; R2 = 24.64% and R2 = 30.07%). Five Klebsiella metabolites were exclusively linked to water samples where oviposition and development occurred. These data suggest metabolomics can be applied to identify compounds potentially used by female Ae. aegypti to evaluate the quality of a breeding site. Elucidating the physiological mechanisms by which the females could integrate these sensory cues while ovipositing constitutes a growing field of interest, which could benefit from a more depurated list of candidate molecules.
The endemic argan tree (Argania spinosa) populations in southern Morocco are highly degraded due to overbrowsing, illegal firewood extraction and the expansion of intensive agriculture. Bare areas between the isolated trees increase due to limited regrowth; however, it is unknown if the trees influence the soil of the intertree areas. Hypothetically, spatial differences in soil parameters of the intertree area should result from the translocation of litter or soil particles (by runoff and erosion or wind drift) from canopy-covered areas to the intertree areas. In total, 385 soil samples were taken around the tree from the trunk along the tree drip line (within and outside the tree area) and the intertree area between two trees in four directions (upslope, downslope and in both directions parallel to the slope) up to 50 m distance from the tree. They were analysed for gravimetric soil water content, pH, electrical conductivity, percolation stability, total nitrogen content (TN), content of soil organic carbon (SOC) and C/N ratio. A total of 74 tension disc infiltrometer experiments were performed near the tree drip line, within and outside the tree area, to measure the unsaturated hydraulic conductivity. We found that the tree influence on its surrounding intertree area is limited, with, e.g., SOC and TN content decreasing significantly from tree trunk (4.4 % SOC and 0.3 % TN) to tree drip line (2.0 % SOC and 0.2 % TN). However, intertree areas near the tree drip line (1.3 % SOC and 0.2 % TN) differed significantly from intertree areas between two trees (1.0 % SOC and 0.1 % TN) yet only with a small effect. Trends for spatial patterns could be found in eastern and downslope directions due to wind drift and slope wash. Soil water content was highest in the north due to shade from the midday sun; the influence extended to the intertree areas. The unsaturated hydraulic conductivity also showed significant differences between areas within and outside the tree area near the tree drip line. This was the case on sites under different land usages (silvopastoral and agricultural), slope gradients or tree densities. Although only limited influence of the tree on its intertree area was found, the spatial pattern around the tree suggests that reforestation measures should be aimed around tree shelters in northern or eastern directions with higher soil water content or TN or SOC content to ensure seedling survival, along with measures to prevent overgrazing.
The Greenlandic oral story-telling tradition, Oqaluttuaq, meaning “history,” “legend,” and “narrative,” is recognized as an important entry point into Arctic collective memory. The graphic artist Nuka K. Godtfredsen and his literary and scientific collaborators have used the term as the title of graphic narratives published from 2009 to 2018, and focused on four moments or ‘snippets’ from Greenland’s history (from the periods of Saqqaq, late Dorset, Norse settlement, and European colonization). Adopting a fragmentary and episodic approach to historical narrativization, the texts frame the modern European presence in Greenland as one of multiple migrations to and settlements in the Artic, rather than its central axis. We argue that, in consequence, the Oqaluttuaq narratives not only “provincialize” the tradition of hyperborean colonial memories, but also provide a postcolonial mnemonic construction of Greenland as a place of multiple histories, plural peoples, and heterogenous temporalities. As such, the books also narrativize loss and disappearance—of people, cultures, and environments-as a distinctive melancholic strand in Greenlandic history. Informed by approaches in the field of cultural memory and in the study memorial objects, Marks’ haptic visuality and Keenan and Weizman’s forensic aesthetics, we analyze the graphic narratives of Oqaluttuaq in regard to their aesthetic dimensions, as well as investigate the role of material objects and artifacts, which work as narrative “props” for multiple stories of encounter and survival in the Arctic.
Background: Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising. Materials and Methods: Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable. Results: PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS. Conclusion: High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.
The specific and precise arrangement of proteins and biomolecules in 3D is an important prerequisite for the study of cell migration, cellular signal transduction and the production of artificial tissue. In a variety of research approaches, proteins have been immobilized on rigid surfaces such as glass or gold to observe protein-protein or protein-cell interactions. While these commonly used analytical platforms offer advantages such as rapid washing steps and easy use, due to their rigidity and two-dimensionality, they cannot replicate the extracellular matrix (ECM) the native environment of cells. This severe deviation from the natural environment results in significant changes in cell structure and cellular processes such as the polarization of the cell, its morphology, and signal transduction. In order to maintain the functionality of the immobilized proteins, it is also enormously important that the proteins are oriented and anchored in the material under mild conditions.
An immobilization strategy that makes this possible is bioaffinity. For this, the specific interaction of a biomolecule with an interaction partner anchored on a surface is used to immobilize the biomolecule. Such an interaction is for example the nitrilotriacetic acid (NTA)/His-tag binding. NTA is a chelator molecule that, when bound to divalent metal ions such as Ni(II), forms an octahedral complex with oligohistidines. The oligo histidine-tag can be competed out of the complex by free histidine or imidazole due to structural similarity. This is exploited in immobilized metal affinity chromatography (IMAC). The binding of a monoNTA/His-tag complex (KD=10 µM) is not stable enough to be used for immobilizations. Therefore, multivalent variants of the chelator were developed, like trisNTA which has a high affinity for His6 tagged proteins (KD= 10 nM). The PA-trisNTA developed in a preliminary work was the first light-activatable system based on the trisNTA chelator head.
The aim of this work was to synthesize a new two-photon (2P) activatable trisNTA (TPA trisNTA) interaction molecule, to analyze its photophysical characteristics and to apply it for two- and three dimensional (2D/3D) biomolecule patterning. The final goal was to use TPA trisNTA for cellular applications in order to manipulate membrane protein organization. Therefore, TPA trisNTA was designed to maintain a stable autoinhibition enabling the immobilization of proteins under physiological conditions with high precision in the x/y, as well as z dimension only upon light activation. 2P activation brings some outstanding advantages: i) the use of near-infrared (NIR) light is less harmful to cells compared to ultraviolet (UV) light, ii) the longer wavelength allows the radiation to penetrate deeper into tissues, iii) the precision of focal irradiation is more accurate because only a focal volume (about 1 fL) is excited and, unlike UV light, scattered light does not lead to activation.
Several backbones for TPA-trisNTA were considered as 2P cleavable groups due to their 2P absorption ability and small size: 3 nitrodibenzofuran (NDBF), 6 bromo 7 hydroxycoumarin (Bhc), and 7 diethylaminocoumarin (DEAC). Initially, suitable synthetic routes were developed for the respective carbaldehydes, since these represented an important intermediate for both the construction of amino acid (aa) derivatives as well as ß hydroxy acids. ß Hydroxy acids were important intermediates because their photocleavage differs from aa derivatives. To establish the conversion from carbaldehydes to hydroxy acids via Reformatsky reaction, commercially available carbaldehydes of the nitroveratral (NV) or nitropiperonal (NP) group were used in addition. The conversion of NDBF, NV, NP proved to be difficult, whereas the ß-hydroxy acid was successfully synthesized from Bhc as well as from DEAC.
Starting from DEAC ß hydroxy acid, a Fmoc protected amino acid derivative was synthesized. To ensure high cleavage efficiency, the DEAC ß hydroxy acid was linked to monoFmoc ethylenediamine through a carbamate linker. Subsequently, the photocleavable group was successfully incorporated into the linker of TPA-trisNTA by solid-phase peptide synthesis (SPPS).
The functional principle of TPA-trisNTA, similar to PA-trisNTA, is based on the autoinhibition of the multivalent chelator head trisNTA, which is linked to an intramolecular oligohistidine sequence by a peptide linker. In presence of Ni(II) ions, trisNTA forms a metal ion-mediated complex with histidine, causing TPA-trisNTA to self-inactivate. The cleavage site is the DEAC based photocleavable amino acid. In contrast to PA-trisNTA, the incorporation of two photocleavable amino acids was omitted. Instead, only one photocleavable DEAC was incorporated in front of the His tag. To avoid a second DEAC group within the His tag, a His5 tag was used instead of an His6 tag. It is known from preliminary work that a His5 tag is sufficient to maintain autoinhibition in the presence of His6-tagged proteins of interest (POIs), but can be displaced from the complex after light-driven cleavage of the peptide backbone. Placement of a cysteine in the peptide linker between the trisNTA and the DEAC group allowed for permanent surface anchoring after photocleavage of the linker.
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The present work deals with photoionization in the realm of the absorption of one single photon. The formal treatment of one-photon ionization usually employs a semi-classical approach, where the electron’s initial and final states are described as quantum-mechanical wave functions but the photon is treated as a classical electromagnetic wave. In the calculation of photoionization cross sections with this semi-classical method, there is an often used approximation which is called the electric dipole approximation. Mathematically, the application of the dipole approximation corresponds to truncating the series expansion of an exponential after the leading term. Physically, this means neglecting the linear photon momentum and the spatial dependence of the light field. The dipole approximation is valid if the wavelength of the light is much larger than the spatial extent of the target and if the photon momentum is small compared to the momenta of the reaction products, which is generally the case for photon energies short above the electron binding energy.
For the present work, we experimentally investigated nondipolar photoionization, i.e., one-photon ionization at high photon energies where the dipole approximation breaks down. In our experiments, we irradiated single atoms and molecules with such high-energetic photons and measured the three-dimensional momentum distributions of the reaction fragments to uncover the effects of the linear photon momentum and the spatially-dependent light field on photoionization. Our observations allow the first profound insight into photoionization that reveals all photon properties, i.e., photon energy, spin, linear momentum, and the speed of light. Hopefully, our efforts make a constructive contribution to the understanding and the further exploration of light-matter interaction.
Late Paleozoic (Variscan) magmatism is widespread in Central Europe. The Lusatian Block is located in the NE Bohemian Massif and it is part of the Saxothuringian Zone of the Variscan orogen. It is bordered by two major NW-trending shear zones, the Intra-Sudetic Fault Zone towards NE and the Elbe Fault Zone towards SW. The scarce Variscan igneous rocks of the Lusatian Block are situated close to these faults. We investigated 19 samples from Variscan plutonic and volcanic rocks of the Lusatian Block, considering all petrological varieties (biotite-bearing granites from the Koenigshain and Stolpen plutons, amphibole-bearing granites from three boreholes, several volcanic dykes, and two volcanites from the intramontane Weissig basin). We applied whole-rock geochemistry (18 samples) and zircon evaporation dating (19 samples). From the evaporation data, we selected six representative samples for additional zircon SHRIMP and CA–ID–TIMS dating. For the Koenigshain pluton, possible protoliths were identified using whole-rock Nd-isotopes, and zircon Hf- and O-isotopes. The new age data allow a subdivision of Variscan igneous rocks in the Lusatian Block into two distinct magmatic episodes. The spatial relation of the two age groups to either the Elbe Fault Zone (298–299 Ma) or the Intra-Sudetic Fault Zone (312–313 Ma) together with reports on the fault-bound character of the dated intrusions suggests an interpretation as two major post-collisional faulting episodes. This assumption of two distinct magmatic periods is confirmed by a compilation of recently published zircon U–Pb CA–ID–TIMS data on further Variscan igneous rocks from the Saxothuringian Zone. New geochemical data allow us to exclude a dominant sedimentary protolith for the Koenigshain pluton as supposed by previous investigations. This conclusion is mainly based on new O- and Hf-isotope data on zircon and the scarcity of inherited zircons. Instead, acid or intermediate igneous rocks are supposed as the main source for these I-type granitoids from the Koenigshain pluton.
Background: Filamentous fungi are excellent lignocellulose degraders, which they achieve through producing carbohydrate active enzymes (CAZymes). CAZyme production is highly orchestrated and gene expression analysis has greatly expanded understanding of this important biotechnological process. The thermophilic fungus Thermoascus aurantiacus secretes highly active thermostable enzymes that enable saccharifications at higher temperatures; however, the genome-wide measurements of gene expression in response to CAZyme induction are not understood. Results: A fed-batch system with plant biomass-derived sugars D-xylose, L-arabinose and cellobiose established that these sugars induce CAZyme expression in T. aurantiacus. The C5 sugars induced both cellulases and hemicellulases, while cellobiose specifically induced cellulases. A minimal medium formulation was developed to enable gene expression studies of T. aurantiacus with these inducers. It was found that d-xylose and L-arabinose strongly induced a wide variety of CAZymes, auxiliary activity (AA) enzymes and carbohydrate esterases (CEs), while cellobiose facilitated lower expression of mostly cellulase genes. Furthermore, putative orthologues of different unfolded protein response genes were up-regulated during the C5 sugar feeding together with genes in the C5 sugar assimilation pathways. Conclusion: This work has identified two additional CAZyme inducers for T. aurantiacus, L-arabinose and cellobiose, along with D-xylose. A combination of biochemical assays and RNA-seq measurements established that C5 sugars induce a suite of cellulases and hemicellulases, providing paths to produce broad spectrum thermotolerant enzymatic mixtures.
Aims: We investigated N471D WASH complex subunit strumpellin (Washc5) knock-in and Washc5 knock-out mice as models for hereditary spastic paraplegia type 8 (SPG8). Methods: We generated heterozygous and homozygous N471D Washc5 knock-in mice and subjected them to a comprehensive clinical, morphological and laboratory parameter screen, and gait analyses. Brain tissue was used for proteomic analysis. Furthermore, we generated heterozygous Washc5 knock-out mice. WASH complex subunit strumpellin expression was determined by qPCR and immunoblotting. Results: Homozygous N471D Washc5 knock-in mice showed mild dilated cardiomyopathy, decreased acoustic startle reactivity, thinner eye lenses, increased alkaline phosphatase and potassium levels and increased white blood cell counts. Gait analyses revealed multiple aberrations indicative of locomotor instability. Similarly, the clinical chemistry, haematology and gait parameters of heterozygous mice also deviated from the values expected for healthy animals, albeit to a lesser extent. Proteomic analysis of brain tissue depicted consistent upregulation of BPTF and downregulation of KLHL11 in heterozygous and homozygous knock-in mice. WASHC5-related protein interaction partners and complexes showed no change in abundancies. Heterozygous Washc5 knock-out mice showing normal WASHC5 levels could not be bred to homozygosity. Conclusions: While biallelic ablation of Washc5 was prenatally lethal, expression of N471D mutated WASHC5 led to several mild clinical and laboratory parameter abnormalities, but not to a typical SPG8 phenotype. The consistent upregulation of BPTF and downregulation of KLHL11 suggest mechanistic links between the expression of N471D mutated WASHC5 and the roles of both proteins in neurodegeneration and protein quality control, respectively.
Diabetes results from a decline in functional pancreatic β-cells, but the molecular mechanisms underlying the pathological β-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces β-cell apoptosis and impaired function. LATS2 deficiency in β-cells and primary isolated human islets as well as β-cell specific LATS2 ablation in mice improves β-cell viability, insulin secretion and β-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in β-cells and genetic and pharmacological inhibition of mTORC1 counteracts the pro-apoptotic action of activated LATS2. We further show a direct interplay between Hippo and autophagy, in which LATS2 is an autophagy substrate. On the other hand, LATS2 regulates β-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating β-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic β-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic β-cell survival and function in diabetes.
Treatment of hexachloropropene (Cl2C[double bond, length as m-dash]C(Cl)–CCl3) with Si2Cl6 and [nBu4N]Cl (1 : 4 : 1) in CH2Cl2 results in a quantitative conversion to the trisilylated, dichlorinated allyl anion salt [nBu4N][Cl2C[double bond, length as m-dash]C(SiCl3)–C(SiCl3)2] ([nBu4N][1]). Tetrachloroallene Cl2C[double bond, length as m-dash]C[double bond, length as m-dash]CCl2 was identified as the first intermediate of the reaction cascade. In the solid state, [1]− adopts approximate Cs symmetry with a dihedral angle between the planes running through the olefinic and carbanionic fragments of [1]− of C[double bond, length as m-dash]C–Si//Si–C–Si = 78.3(1)°. One-electron oxidation of [nBu4N][1] with SbCl5 furnishes the distillable blue radical 1˙. The neutral propene Cl2C[double bond, length as m-dash]C(SiCl3)–C(SiCl3)2H (2) was obtained by (i) protonation of [1]− with HOSO2CF3 (HOTf) or (ii) H-atom transfer to 1˙ from 1,4-cyclohexadiene. Quantitative transformation of all three SiCl3 substituents in 2 to Si(OMe)3 (2OMe) or SiMe3 (2Me) substituents was achieved by using MeOH/NMe2Et or MeMgBr in CH2Cl2 or THF, respectively. Upon addition of 2 equiv. of tBuLi, 2Me underwent deprotonation with subsequent LiCl elimination, 1,2-SiMe3 migration and Cl/Li exchange to afford the allenyl lithium compound Me3Si(Li)C[double bond, length as m-dash]C[double bond, length as m-dash]C(SiMe3)2 (Li[4]), which is an efficient building block for the introduction of Me, SiMe3, or SnMe3 (5) groups. The trisilylated, monochlorinated allene Cl3Si(Cl)C[double bond, length as m-dash]C[double bond, length as m-dash]C(SiCl3)2 (6), was obtained from [nBu4N][1] through Cl−-ion abstraction with AlCl3 and rearrangement in CH2Cl2 (1˙ forms as a minor side product, likely because the system AlCl3/CH2Cl2 can also act as a one-electron oxidant).
Digital distractions can interfere with goal attainment and lead to undesirable habits that are hard to get red rid of. Various digital self-control interventions promise support to alleviate the negative impact of digital distractions. These interventions use different approaches, such as the blocking of apps and websites, goal setting, or visualizations of device usage statistics. While many apps and browser extensions make use of these features, little is known about their effectiveness. This systematic review synthesizes the current research to provide insights into the effectiveness of the different kinds of interventions. From a search of the ‘ACM’, ‘Springer Link’, ‘Web of Science’, ’IEEE Xplore’ and ‘Pubmed’ databases, we identified 28 digital self-control interventions. We categorized these interventions according to their features and their outcomes. The interventions showed varying degrees of effectiveness, and especially interventions that relied purely on increasing the participants' awareness were barely effective. For those interventions that sanctioned the use of distractions, the current literature indicates that the sanctions have to be sufficiently difficult to overcome, as they will otherwise be quickly dismissed. The overall confidence in the results is low, with small sample sizes, short study duration, and unclear study contexts. From these insights, we highlight research gaps and close with suggestions for future research.
The article “Integrity of dural closure after autologous platelet rich fibrin augmentation: an in vitro study”, written by Vasilikos, I., Beck, J., Ghanaati, S., Grauvogel, J., Nisyrios, T., Grapatsas, K., and Hubbe, U., was originally published Online First without Open Access. After publication in volume 162, issue 4, page 737–743 the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2020 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0. Open access funding enabled and organized by Projekt DEAL.
Background and purpose: During acute coronavirus disease 2019 (COVID-19) infection, neurological signs, symptoms and complications occur. We aimed to assess their clinical relevance by evaluating real-world data from a multinational registry. Methods: We analyzed COVID-19 patients from 127 centers, diagnosed between January 2020 and February 2021, and registered in the European multinational LEOSS (Lean European Open Survey on SARS-Infected Patients) registry. The effects of prior neurological diseases and the effect of neurological symptoms on outcome were studied using multivariate logistic regression. Results: A total of 6537 COVID-19 patients (97.7% PCR-confirmed) were analyzed, of whom 92.1% were hospitalized and 14.7% died. Commonly, excessive tiredness (28.0%), headache (18.5%), nausea/emesis (16.6%), muscular weakness (17.0%), impaired sense of smell (9.0%) and taste (12.8%), and delirium (6.7%) were reported. In patients with a complicated or critical disease course (53%) the most frequent neurological complications were ischemic stroke (1.0%) and intracerebral bleeding (ICB; 2.2%). ICB peaked in the critical disease phase (5%) and was associated with the administration of anticoagulation and extracorporeal membrane oxygenation (ECMO). Excessive tiredness (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.20–1.68) and prior neurodegenerative diseases (OR 1.32, 95% CI 1.07–1.63) were associated with an increased risk of an unfavorable outcome. Prior cerebrovascular and neuroimmunological diseases were not associated with an unfavorable short-term outcome of COVID-19. Conclusion: Our data on mostly hospitalized COVID-19 patients show that excessive tiredness or prior neurodegenerative disease at first presentation increase the risk of an unfavorable short-term outcome. ICB in critical COVID-19 was associated with therapeutic interventions, such as anticoagulation and ECMO, and thus may be an indirect complication of a life-threatening systemic viral infection.
RATIONALE: RBPs (RNA-binding proteins) play critical roles in human biology and disease. Aberrant RBP expression affects various steps in RNA processing, altering the function of the target RNAs. The RBP SRSF4 (serine/arginine-rich splicing factor 4) has been linked to neuropathies and cancer. However, its role in the heart is completely unknown. OBJECTIVE: To investigate the role of SRSF4 in the heart. METHODS AND RESULTS: Echocardiography of mice specifically lacking SRSF4 in the heart (SRSF4 KO) revealed left ventricular hypertrophy and increased cardiomyocyte area, which led to progressive diastolic dysfunction with age. SRSF4 KO mice showed altered electrophysiological activity under isoproterenol-induced cardiac stress, with a post-QRS depression and a longer QT interval, indicating an elevated risk of sudden cardiac death. RNA-Seq analysis revealed expression changes in several long noncoding RNAs, including GAS5 (growth arrest-specific 5), which we identified as a direct SRSF4 target in cardiomyocytes by individual-nucleotide- resolution cross-linking and immuno-precipitation. GAS5 is a repressor of the GR (glucocorticoid receptor) and was downregulated in SRSF4 KO hearts. This corresponded with elevated GR transcriptional activity in cardiomyocytes, leading to increases in hypertrophy markers and cell size. Furthermore, hypertrophy in SRSF4 KO cardiomyocytes was reduced by overexpressing GAS5. CONCLUSIONS: Loss of SRSF4 expression results in cardiac hypertrophy, diastolic dysfunction, and abnormal repolarization. The molecular mechanism underlying this effect involves GAS5 downregulation and consequent elevation of GR transcriptional activity. Our findings may help to develop new therapeutic tools for the treatment of cardiac hypertrophy and myocardial pathology in patients with Cushing syndrome.
Aim: The identification of the mechanisms determining spatial variation in biological diversity along elevational gradients is a central objective in ecology and biogeography. Here, we disentangle the direct and indirect effects of abiotic drivers (climatic conditions, and land use) and biotic drivers (vegetation structure and food resources) on functional diversity and composition of bird and bat assemblages along a tropical elevational gradient. Location: Southern slopes of Mt. Kilimanjaro, Tanzania, East Africa. Methods: We counted birds and recorded bat sonotypes on 58 plots distributed in near-natural and anthropogenically modified habitats from 700 to 4,600 m above sea level. For the recorded taxa, we compiled functional traits related to movement, foraging and body size from museum specimens and databases. Further, we recorded mean annual temperature, precipitation, vegetation complexity as well as the number of fruits, flowers, and insect biomass as measures of resource availability on each study site. Results: Using path analyses, we found similar responses of bird and bat functional diversity to the variation in abiotic and biotic drivers along the elevational gradient. In contrast, the functional composition of both taxa showed distinct responses to abiotic and biotic drivers. For both groups, direct temperature effects were most important, followed by resource availability, precipitation and vegetation complexity. Main Conclusions: Our findings indicate that physiological and metabolic constraints imposed by temperature and resource availability determine the functional diversity of bird and bat assemblages, whereas the composition of individual functional traits is driven by taxon-specific processes. Our study illustrates that distinct filtering mechanisms can result in similar patterns of functional diversity along broad environmental gradients. Such differences need to be taken into account when it comes to conserving the functional diversity of flying vertebrates on tropical mountains.
Purpose: The prospective, randomized ERGO2 trial investigated the effect of calorie-restricted ketogenic diet and intermittent fasting (KD-IF) on re-irradiation for recurrent brain tumors. The study did not meet its primary endpoint of improved progression-free survival in comparison to standard diet (SD). We here report the results of the quality of life/neurocognition and a detailed analysis of the diet diaries. Methods: 50 patients were randomized 1:1 to re-irradiation combined with either SD or KD-IF. The KD-IF schedule included 3 days of ketogenic diet (KD: 21–23 kcal/kg/d, carbohydrate intake limited to 50 g/d), followed by 3 days of fasting and again 3 days of KD. Follow-up included examination of cognition, quality of life and serum samples. Results: The 20 patients who completed KD-IF met the prespecified goals for calorie and carbohydrate restriction. Substantial decreases in leptin and insulin and an increase in uric acid were observed. The SD group, of note, had a lower calorie intake than expected (21 kcal/kg/d instead of 30 kcal/kg/d). Neither quality of life nor cognition were affected by the diet. Low glucose emerged as a significant prognostic parameter in a best responder analysis. Conclusion: The strict caloric goals of the ERGO2 trial were tolerated well by patients with recurrent brain cancer. The short diet schedule led to significant metabolic changes with low glucose emerging as a candidate marker of better prognosis. The unexpected lower calorie intake of the control group complicates the interpretation of the results. Clinicaltrials.gov number: NCT01754350; Registration: 21.12.2012.
Introduction: Deep brain stimulation (DBS) has become a well-established treatment modality for a variety of conditions over the last decades. Multiple surgeries are an essential part in the postoperative course of DBS patients if nonrechargeable implanted pulse generators (IPGs) are applied. So far, the rate of subclinical infections in this field is unknown. In this prospective cohort study, we used sonication to evaluate possible microbial colonization of IPGs from replacement surgery. Methods: All consecutive patients undergoing IPG replacement between May 1, 2019 and November 15, 2020 were evaluated. The removed hardware was investigated using sonication to detect biofilm-associated bacteria. Demographic and clinical data were analyzed. Results: A total of 71 patients with a mean (±SD) of 64.5 ± 15.3 years were evaluated. In 23 of these (i.e., 32.4%) patients, a positive sonication culture was found. In total, 25 microorganisms were detected. The most common isolated microorganisms were Cutibacterium acnes (formerly known as Propionibacterium acnes) (68%) and coagulase-negative Staphylococci (28%). Within the follow-up period (5.2 ± 4.3 months), none of the patients developed a clinical manifest infection. Discussions/Conclusions: Bacterial colonization of IPGs without clinical signs of infection is common but does not lead to manifest infection. Further larger studies are warranted to clarify the impact of low-virulent pathogens in clinically asymptomatic patients.
Aims: To compare the effects of Ayurvedic and conventional nutritional therapy in patients with irritable bowel syndrome (IBS). Methods: Sixty-nine patients with IBS were randomized to Ayurvedic (n = 35) or conventional nutritional therapy according to the recommendations of the German Nutrition Society including the low-FODMAP diet (n = 34). Study visits took place at baseline and after 1, 3, and 6 months. The primary outcome was IBS symptom severity (IBS-SSS) after 3 months; secondary outcomes included stress (CPSS), anxiety and depression (HADS), well-being (WHO-5) and IBS-specific quality of life (IBS-QOL). A repeated measures general linear model (GLM) for intent-to-treat-analyses was applied in this explorative study. Results: After 3 months, estimated marginal means for IBS-SSS reductions were 123.8 [95% confidence interval (95% CI) = 92.8–154.9; p < 0.001] in the Ayurvedic and 72.7 (95% CI = 38.8–106.7; p < 0.001) in the conventional group. The IBS-SSS reduction was significantly higher in the Ayurveda group compared to the conventional therapy group (estimated marginal mean = 51.1; 95% CI = 3.8–98.5; p = 0.035) and clinically meaningful. Sixty-eight percentage of the variance in IBS-SSS reduction after 3 months can be explained by treatment, 6.5% by patients' expectations for their therapies and 23.4% by IBS-SSS at pre-intervention. Both therapies are equivalent in their contribution to the outcome variance. The higher the IBS-SSS score at pre-intervention and the larger the patients' expectations, the greater the IBS-SSS reduction. There were no significant group differences in any secondary outcome measures. No serious adverse events occurred in either group. Conclusion: Patients with IBS seem to benefit significantly from Ayurvedic or conventional nutritional therapy. The results warrant further studies with longer-term follow-ups and larger sample sizes. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03019861, identifier: NCT03019861.
China’s law to control international non-governmental organisations (INGOs) has sent shockwaves through international non-governmental organisations (NGOs), civil society and expert communities as the epitome of a worldwide trend of closing civic spaces. Since the Overseas NGO Management Law was enacted in January 2017, its implementation has seen mixed effects and diverging patterns of adaptation among Chinese party-state actors at the central and local levels and among domestic NGOs and INGOs. To capture the formal and informal dynamics underlying their mutual interactions in the longer term, this article employs a theory of institutional change inspired by Elinor Ostrom’s distinction between rules-in-form versus rules-in-use and identifies four scenarios for international civil society in China – “no change,” “restraining,” “recalibrating” and “reorienting.” Based on interviews, participant observation and Chinese policy documents and secondary literature, the respective driving forces, plausibility, likelihood and longer-term implications of each scenario are assessed. It is found that INGOs’ activities are increasingly affected by the international ambitions of the Chinese party-state, which enmeshes both domestic NGOs and INGOs as agents in its diplomatic efforts to redefine civil society participation on a global scale.
Visual working memory (VWM) is reliably predictive of fluid intelligence and academic achievements. The objective of the current study was to investigate individual differences in pre-schoolers’ VWM processing by examining the association between behaviour, brain function and parent-reported measures related to the child's environment. We used a portable functional near-infrared spectroscopy system to record from the frontal and parietal cortices of 4.5-year-old children (N = 74) as they completed a colour change-detection VWM task in their homes. Parents were asked to fill in questionnaires on temperament, academic aspirations, home environment and life stress. Children were median-split into a low-performing (LP) and a high-performing (HP) group based on the number of items they could successfully remember during the task. LPs increasingly activated channels in the left frontal and bilateral parietal cortices with increasing load, whereas HPs showed no difference in activation. Our findings suggest that LPs recruited more neural resources than HPs when their VWM capacity was challenged. We employed mediation analyses to examine the association between the difference in activation between the highest and lowest loads and variables from the questionnaires. The difference in activation between loads in the left parietal cortex partially mediated the association between parent-reported stressful life events and VWM performance. Critically, our findings show that the association between VWM capacity, left parietal activation and indicators of life stress is important to understand the nature of individual differences in VWM in pre-school children.
Photoacids attract increasing scientific attention, as they are valuable tools to spatiotemporally control proton-release reactions and pH values of solutions. We present the first time-resolved spectroscopic study of the excited state and proton-release dynamics of prominent merocyanine representatives. Femtosecond transient absorption measurements of a pyridine merocyanine with two distinct protonation sites revealed dissimilar proton-release mechanisms: one site acts as a photoacid generator as its pKa value is modulated in the ground state after photoisomerization, while the other functions as an excited state photoacid which releases its proton within 1.1 ps. With a pKa drop of 8.7 units to −5.5 upon excitation, the latter phenolic site is regarded a super-photoacid. The 6-nitro derivative exhibits only a phenolic site with similar, yet slightly less photoacidic characteristics and both compounds transfer their proton to methanol and ethanol. In contrast, for the related 6,8-dinitro compound an intramolecular proton transfer to the ortho-nitro group is suggested that is involved in a rapid relaxation into the ground state.
Gender and attitudes toward welfare state reform: Are women really social investment promoters?
(2021)
This article contributes to the study of the demand side of welfare politics by investigating gender differences in social investment preferences systematically. Building on the different functions of social investment policies in creating, preserving, or mobilizing skills, we argue that women do not support social investment policies generally more strongly than men. Rather, women demand, in particular, policies to preserve their skills during career interruptions and help to mobilize their skills on the labour market. In a second analytical step, we examine women’s policy priorities if skill preservation and mobilization come at the expense of social compensation. We test our arguments for eight Western European countries with data from the INVEDUC survey. The confirmation of our arguments challenges a core assumption of the literatures on the social investment turn and women’s political realignment. We discuss the implication of our findings in the conclusion.
In psychiatry, there has been a growing focus on identifying at-risk populations. For schizophrenia, these efforts have led to the development of early recognition and intervention measures. Despite a similar disease burden, the populations at risk of bipolar disorder have not been sufficiently characterized. Within the BipoLife consortium, we used magnetic resonance imaging (MRI) data from a multicenter study to assess structural gray matter alterations in N = 263 help-seeking individuals from seven study sites. We defined the risk using the EPIbipolar assessment tool as no-risk, low-risk, and high-risk and used a region-of-interest approach (ROI) based on the results of two large-scale multicenter studies of bipolar disorder by the ENIGMA working group. We detected significant differences in the thickness of the left pars opercularis (Cohen’s d = 0.47, p = 0.024) between groups. The cortex was significantly thinner in high-risk individuals compared to those in the no-risk group (p = 0.011). We detected no differences in the hippocampal volume. Exploratory analyses revealed no significant differences in other cortical or subcortical regions. The thinner cortex in help-seeking individuals at risk of bipolar disorder is in line with previous findings in patients with the established disorder and corresponds to the region of the highest effect size in the ENIGMA study of cortical alterations. Structural alterations in prefrontal cortex might be a trait marker of bipolar risk. This is the largest structural MRI study of help-seeking individuals at increased risk of bipolar disorder.
Periodontal furcation lesions: a survey of diagnosis and management by general dental practitioners
(2021)
Aim: The aim of this study was to explore general dental practitioners' (GDPs) attitude to periodontal furcation involvement (FI). Materials and methods: An online survey focused on diagnosis and management of periodontal FI was circulated to GDPs in seven different countries. Results: A total of 400 responses were collected. Nearly a fifth of participants reported rarely or never taking 6-point pocket charts; 65.8% of participants had access to a Nabers probe in their practice. When shown clinical pictures and radiographs of FI-involved molars, the majority of participants correctly diagnosed it. Although 47.1% of participants were very/extremely confident in detecting FI, only 8.9% felt very/extremely confident at treating it. Differences in responses were detected according to country and year of qualification, with a trend towards less interest in periodontal diagnosis and treatment in younger generations. Lack of knowledge of management/referral pathways (reported by 22.8%) and lack of correct equipment were considered the biggest barriers to FI management. Most participants (80.9%) were interested in learning more about FI, ideally face to face followed by online tutorials. Conclusions: Plans should be put in place to improve general dentists' knowledge and ability to manage FI, as this can have a significant impact on public health.
Cytochrome P450 (CYP) signalling pathway has been shown to play a vital role in the vasoreactivity of wild type mouse ophthalmic artery. In this study, we determined the expression, vascular responses and potential mechanisms of the CYP-derived arachidonic acid metabolites. The expression of murine CYP (Cyp2c44) and soluble epoxide hydrolase (sEH) in the wild type ophthalmic artery was determined with immunofluorescence, which showed predominant expression of Cyp2c44 in the vascular smooth muscle cells (VSMC), while sEH was found mainly in the endothelium of the wild type ophthalmic artery. Artery of Cyp2c44−/− and sEH−/− mice were used as negative controls. Targeted mass spectrometry-based lipidomics analysis of endogenous epoxide and diols of the wild type artery detected only 14, 15-EET. Vasorelaxant responses of isolated vessels in response to selective pharmacological blockers and agonist were analysed ex vivo. Direct antagonism of epoxyeicosatrienoic acids (EETs) with a selective inhibitor caused partial vasodilation, suggesting that EETs may behave as vasoconstrictors. Exogenous administration of synthetic EET regioisomers significantly constricted the vessels in a concentration-dependent manner, with the strongest responses elicited by 11, 12- and 14, 15-EETs. Our results provide the first experimental evidence that Cyp2c44-derived EETs in the VSMC mediate vasoconstriction of the ophthalmic artery.
U–Pb age spectra of detrital zircons related to the East European Platform could be traced in paragneiss through the whole Mid-German-Crystalline Zone (Variscides, Central Europe) from the Odenwald via the Spessart to the Ruhla crystalline forming an exotic unit between Armorica and Laurussia. The depositional ages of the paragneiss are defined by the youngest age of the detrital zircons and the oldest intrusion ages as Ordovician to Silurian. The Ediacaran dominated age spectrum of detrital zircons from the paragneiss of the East Odenwald suggests the latter to be derived from the shelf of the East European Platform (Baltica), which was influenced by the 1.5 Ga old detritus delivered from a giant intrusion (Mazury granitoid, Poland). The detrital zircon age spectrum of the lower Palaeozoic paragneiss of the East Odenwald and sandstone of the northern Holy Cross Mountains are identical. The pure Sveconorwegian spectrum of the lower Palaeozoic quartzite from the Spessart, (Kirchner and Albert Int J Earth Sci 2020) and the Ruhla (Zeh and Gerdes Gondwana Res 17:254–263, 2010) could be sourced from Bornholm and southern Sweden. A U–Pb age spectrum with 88% Palaeozoic detrital zircons from a volcano-sedimentary rock of the East Odenwald is interpreted to be derived from a Silurian magmatic arc (46%), which was probably generated during the drift of the Mid-German-Crystalline Zone micro-continent to the south. A tentative plate tectonic model of Mid-German-Crystalline Zone is presented taking into account (a) the East European Platform related age spectra of the detrital zircons (b) the Ordovician to Silurian depositional age of the metasediments (c) the Silurian and Early Devonian intrusion age of the plutonic and volcanic rocks and (d) the U–Pb ages of the Middle Devonian high-grade metamorphism. The East European Platform-related part of the Mid-German-Crystalline Zone is interpreted as a micro-continent, which drifted through the Rheic Ocean to the south and collided with the Saxothuringian (Armorican Terrane Assemblage) during the Early Devonian. Such large-scale tectonic transport from the northern continent to the southern continent is also known from the SW Iberia, where Laurussia-related metasediments of the Rheic suture zone are explained by a large scale tectonic escape (Braid et al. J Geol Soc Lond 168:383–392, 2011).