Large-scale databases that report the inhibitory capacities of many combinations of candidate drug compounds and cultivated cancer cell lines have driven the development of preclinical drug-sensitivity models based on machine learning. However, cultivated cell lines have devolved from human cancer cells over years or even decades under selective pressure in culture conditions. Moreover, models that have been trained on in vitro data cannot account for interactions with other types of cells. Drug-response data that are based on patient-derived cell cultures, xenografts, and organoids, on the other hand, are not available in the quantities that are needed to train high-capacity machine-learning models. We found that pre-training deep neural network models of drug sensitivity on in vitro drug-sensitivity databases before fine-tuning the model parameters on patient-derived data improves the models’ accuracy and improves the biological plausibility of the features, compared to training only on patient-derived data. From our experiments, we can conclude that pre-trained models outperform models that have been trained on the target domains in the vast majority of cases.

Background Animal personality has emerged as a key concept in behavioral ecology. While many studies have demonstrated the influence of personality traits on behavioral patterns, its quantification, especially in wild animal populations, remains a challenge. Only a few studies have established a link between personality and recurring movements within home ranges, although these small-scale movements are of key importance for identifying ecological interactions and forming individual niches. In this regard, differences in space use among individuals might reflect different exploration styles between behavioral types along the shy-bold continuum. Methods We assessed among-individual differences in behavior in the European hare (Lepus europaeus), a characteristic mammalian herbivore in agricultural landscapes using a standardized box emergence test for captive and wild hares. We determined an individuals’ degree of boldness by measuring the latencies of behavioral responses in repeated emergence tests in captivity. During capture events of wild hares, we conducted a single emergence test and recorded behavioral responses proven to be stable over time in captive hares. Applying repeated novel environment tests in a near-natural enclosure, we further quantified aspects of exploration and activity in captive hares. Finally, we investigated whether and how this among-individual behavioral variation is related to general activity and space use in a wild hare population. Wild and captive hares were treated similarly and GPS-collared with internal accelerometers prior to release to the wild or the outdoor enclosure, respectively. General activity was quantified as overall dynamic body acceleration (ODBA) obtained from accelerometers. Finally, we tested whether boldness explained variation in (i) ODBA in both settings and (ii) variation in home ranges and core areas across different time scales of GPS-collared hares in a wild population. Results We found three behavioral responses to be consistent over time in captive hares. ODBA was positively related to boldness (i.e., short latencies to make first contact with the new environment) in both captive and wild hares. Space use in wild hares also varied with boldness, with shy individuals having smaller core areas and larger home ranges than bold conspecifics (yet in some of the parameter space, this association was just marginally significant). Conclusions Against our prediction, shy individuals occupied relatively large home ranges but with small core areas. We suggest that this space use pattern is due to them avoiding risky, and energy-demanding competition for valuable resources. Carefully validated, activity measurements (ODBA) from accelerometers provide a valuable tool to quantify aspects of animal personality along the shy-bold continuum remotely. Without directly observing—and possibly disturbing—focal individuals, this approach allows measuring variability in animal personality, especially in species that are difficult to assess with experiments. Considering that accelerometers are often already built into GPS units, we recommend activating them at least during the initial days of tracking to estimate individual variation in general activity and, if possible, match them with a simple novelty experiment. Furthermore, information on individual behavioral types will help to facilitate mechanistic understanding of processes that drive spatial and ecological dynamics in heterogeneous landscapes.

The importance of carbohydrate structures is enormous due to their ubiquitousness in our lives. The development of so-called glycomaterials is the result of this tremendous significance. These are not exclusively used for research into fundamental biological processes, but also, among other things, as inhibitors of pathogens or as drug delivery systems. This work describes the development of glycomaterials involving the synthesis of glycoderivatives, -monomers and -polymers. Glycosylamines were synthesized as precursors in a single synthesis step under microwave irradiation to significantly shorten the usual reaction time. Derivatization at the anomeric position was carried out according to the methods developed by Kochetkov and Likhorshetov, which do not require the introduction of protecting groups. Aminated saccharide structures formed the basis for the synthesis of glycomonomers in β-configuration by methacrylation. In order to obtain α-Man-based monomers for interactions with certain α-Man-binding lectins, a monomer synthesis by Staudinger ligation was developed in this work, which also does not require protective groups. Modification of the primary hydroxyl group of a saccharide was accomplished by enzyme-catalyzed synthesis. Ribose-containing cytidine was transesterified using the lipase Novozym 435 and microwave irradiation. The resulting monomer synthesis was optimized by varying the reaction partners. To create an amide bond instead of an ester bond, protected cytidine was modified by oxidation followed by amide coupling to form the monomer. This synthetic route was also used to isolate the monomer from its counterpart guanosine. After obtaining the nucleoside-based monomers, they were block copolymerized using the RAFT method. Pre-synthesized pHPMA served as macroCTA to yield cytidine- or guanosine-containing block copolymer. These isolated block copolymers were then investigated for their self-assembly behavior using UV-Vis, DLS and SEM to serve as a potential thermoresponsive drug delivery system.

Diabetes is hallmarked by high blood glucose levels, which cause progressive generalised vascular damage, leading to microvascular and macrovascular complications. Diabetes-related complications cause severe and prolonged morbidity and are a major cause of mortality among people with diabetes. Despite increasing attention to risk factors of type 2 diabetes, existing evidence is scarce or inconclusive regarding vascular complications and research investigating both micro- and macrovascular complications is lacking. This thesis aims to contribute to current knowledge by identifying risk factors – mainly related to lifestyle – of vascular complications, addressing methodological limitations of previous literature and providing comparative data between micro- and macrovascular complications. To address this overall aim, three specific objectives were set. The first was to investigate the effects of diabetes complication burden and lifestyle-related risk factors on the incidence of (further) complications. Studies suggest that diabetes complications are interrelated. However, they have been studied mainly independently of individuals’ complication burden. A five-state time-to-event model was constructed to examine the longitudinal patterns of micro- (kidney disease, neuropathy and retinopathy) and macrovascular complications (myocardial infarction and stroke) and their association with the occurrence of subsequent complications. Applying the same model, the effect of modifiable lifestyle factors, assessed alone and in combination with complication load, on the incidence of diabetes complications was studied. The selected lifestyle factors were body mass index (BMI), waist circumference, smoking status, physical activity, and intake of coffee, red meat, whole grains, and alcohol. Analyses were conducted in a cohort of 1199 participants with incident type 2 diabetes from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam, who were free of vascular complications at diabetes diagnosis. During a median follow-up time of 11.6 years, 96 cases of macrovascular complications (myocardial infarction and stroke) and 383 microvascular complications (kidney disease, neuropathy and retinopathy) were identified. In multivariable-adjusted models, the occurrence of a microvascular complication was associated with a higher incidence of further micro- (Hazard ratio [HR] 1.90; 95% Confidence interval [CI] 0.90, 3.98) and macrovascular complications (HR 4.72; 95% CI 1.25, 17.68), compared with persons without a complication burden. In addition, participants who developed a macrovascular event had a twofold higher risk of future microvascular complications (HR 2.26; 95% CI 1.05, 4.86). The models were adjusted for age, sex, state duration, education, lifestyle, glucose-lowering medication, and pre-existing conditions of hypertension and dyslipidaemia. Smoking was positively associated with macrovascular disease, while an inverse association was observed with higher coffee intake. Whole grain and alcohol intake were inversely associated with microvascular complications, and a U-shaped association was observed for red meat intake. BMI and waist circumference were positively associated with microvascular events. The associations between lifestyle factors and incidence of complications were not modified by concurrent complication burden, except for red meat intake and smoking status, where the associations were attenuated among individuals with a previous complication. The second objective was to perform an in-depth investigation of the association between BMI and BMI change and risk of micro- and macrovascular complications. There is an ongoing debate on the association between obesity and risk of macrovascular and microvascular outcomes in type 2 diabetes, with studies suggesting a protective effect among people with overweight or obesity. These findings, however, might be limited due to suboptimal control for smoking, pre-existing chronic disease, or short-follow-up. After additional exclusion of persons with cancer history at diabetes onset, the associations between pre-diagnosis BMI and relative annual change between pre- and post-diagnosis BMI and incidence of complications were evaluated in multivariable-adjusted Cox models. The analyses were adjusted for age, sex, education, smoking status and duration, physical activity, alcohol consumption, adherence to the Mediterranean diet, and family history of diabetes and cardiovascular disease (CVD). Among 1083 EPIC-Potsdam participants, 85 macrovascular and 347 microvascular complications were identified during a median follow-up period of 10.8 years. Higher pre-diagnosis BMI was associated with an increased risk of total microvascular complications (HR per 5 kg/m2 1.21; 95% CI 1.07, 1.36), kidney disease (HR 1.39; 95% CI 1.21, 1.60) and neuropathy (HR 1.12; 95% CI 0.96, 1.31); but no association was observed for macrovascular complications (HR 1.05; 95% CI 0.81, 1.36). Effect modification was not evident by sex, smoking status, or age groups. In analyses according to BMI change categories, BMI loss of more than 1% indicated a decreased risk of total microvascular complications (HR 0.62; 95% CI 0.47, 0.80), kidney disease (HR 0.57; 95% CI 0.40, 0.81) and neuropathy (HR 0.73; 95% CI 0.52, 1.03), compared with participants with a stable BMI. No clear association was observed for macrovascular complications (HR 1.04; 95% CI 0.62, 1.74). The impact of BMI gain on diabetes-related vascular disease was less evident. Associations were consistent across strata of age, sex, pre-diagnosis BMI, or medication but appeared stronger among never-smokers than current or former smokers. The last objective was to evaluate whether individuals with a high-risk profile for diabetes and cardiovascular disease (CVD) also have a greater risk of complications. Within the EPIC-Potsdam study, two accurate prognostic tools were developed, the German Diabetes Risk Score (GDRS) and the CVD Risk Score (CVDRS), which predict the 5-year type 2 diabetes risk and 10-year CVD risk, respectively. Both scores provide a non-clinical and clinical version. Components of the risk scores include age, sex, waist circumference, prevalence of hypertension, family history of diabetes or CVD, lifestyle factors, and clinical factors (only in clinical versions). The association of the risk scores with diabetes complications and their discriminatory performance for complications were assessed. In crude Cox models, both versions of GDRS and CVDRS were positively associated with macrovascular complications and total microvascular complications, kidney disease and neuropathy. Higher GDRS was also associated with an elevated risk of retinopathy. The discrimination of the scores (clinical and non-clinical) was poor for all complications, with the C-index ranging from 0.58 to 0.66 for macrovascular complications and from 0.60 to 0.62 for microvascular complications. In conclusion, this work illustrates that the risk of complication development among individuals with type 2 diabetes is related to the existing complication load, and attention should be given to regular monitoring for future complications. It underlines the importance of weight management and adherence to healthy lifestyle behaviours, including high intake of whole grains, moderation in red meat and alcohol consumption and avoidance of smoking to prevent major diabetes-associated complications, regardless of complication burden. Risk scores predictive for type 2 diabetes and CVD were related to elevated risks of complications. By optimising several lifestyle and clinical factors, the risk score can be improved and may assist in lowering complication risk.

The increasing demand for energy in the current technological era and the recent political decisions about giving up on nuclear energy diverted humanity to focus on alternative environmentally friendly energy sources like solar energy. Although silicon solar cells are the product of a matured technology, the search for highly efficient and easily applicable materials is still ongoing. These properties made the efficiency of halide perovskites comparable with silicon solar cells for single junctions within a decade of research. However, the downside of halide perovskites are poor stability and lead toxicity for the most stable ones. On the other hand, chalcogenide perovskites are one of the most promising absorber materials for the photovoltaic market, due to their elemental abundance and chemical stability against moisture and oxygen. In the search of the ultimate solar absorber material, combining the good optoelectronic properties of halide perovskites with the stability of chalcogenides could be the promising candidate. Thus, this work investigates new techniques for the synthesis and design of these novel chalcogenide perovskites, that contain transition metals as cations, e.g., BaZrS3, BaHfS3, EuZrS3, EuHfS3 and SrHfS3. There are two stages in the deposition techniques of this study: In the first stage, the binary compounds are deposited via a solution processing method. In the second stage, the deposited materials are annealed in a chalcogenide atmosphere to form the perovskite structure by using solid-state reactions. The research also focuses on the optimization of a generalized recipe for a molecular ink to deposit precursors of chalcogenide perovskites with different binaries. The implementation of the precursor sulfurization resulted in either binaries without perovskite formation or distorted perovskite structures, whereas some of these materials are reported in the literature as they are more favorable in the needle-like non-perovskite configuration. Lastly, there are two categories for the evaluation of the produced materials: The first category is about the determination of the physical properties of the deposited layer, e.g., crystal structure, secondary phase formation, impurities, etc. For the second category, optoelectronic properties are measured and compared to an ideal absorber layer, e.g., band gap, conductivity, surface photovoltage, etc.

RESUME Cette etude propose d'explorer et d'identifier des moments particuliers oU le changement linguistique se produit, afin de confirmer ou de rejeter l'idee d'une periode specifique designee par le terme << francais preclassique >>, avec une rupture - ou frontiere chronolectale - detectable autour de 1630 (cf. Ayres-Bennett et Caron, 2016). Afin de verifier dans quelle mesure cette chronologie peut etre confirmee, il est necessaire de multiplier des analyses fines et pointues sur des traits linguistiques qui ont subi des changements a l'epoque en question et d'interroger une gamme de textes qui refletent la variation discursive et pragmatique, au lieu de consulter le canon des traditions textuelles actuellement disponibles sur des bases numerisees, qui sont essentiellement litteraires. C'est pourquoi nous avons consulte des sources de nature differente, qui pourraient attester des usages emergents, a savoir les corpus du Reseau Corpus Francais Preclassique et Classique (RCFC). Seront presentes les resultats de deux etudes de cas (la recategorisation des formes dedans/dessous/dessus/dehors et la montee des clitiques), abondamment discutes par les remarqueurs.

This volume deals with different linguistic phenomena representing grammaticalization and lexicalization processes and combines different approaches of contact linguistics and variational linguistics. It contains papers on clitic placement in Angolan Portuguese, on the use of subject pronouns in French, Brazilian Portuguese and Caribbean Spanish, on evidential marking in Paraguayan Spanish, on Paraguayan Guaraní, on evidentiality in different varieties of Spanish, on discourse markers in Latin America, on modal particles in Italian and their translation into German, on bilingual communities in Southern Brazil, on Spanish-German-Russian language contact and on Romance aspectual periphrases in contact with English progressives.

This work introduces an embedded approach for the prediction of Solar Particle Events (SPEs) in space applications by combining the real-time Soft Error Rate (SER) measurement with SRAM-based detector and the offline trained machine learning model. The proposed approach is intended for the self-adaptive fault-tolerant multiprocessing systems employed in space applications. With respect to the state-of-the-art, our solution allows for predicting the SER 1 h in advance and fine-grained hourly tracking of SER variations during SPEs as well as under normal conditions. Therefore, the target system can activate the appropriate mechanisms for radiation hardening before the onset of high radiation levels. Based on the comparison of five different machine learning algorithms trained with the public space flux database, the preliminary results indicate that the best prediction accuracy is achieved with the recurrent neural network (RNN) with long short-term memory (LSTM).

Advanced non-viral gene delivery experiments often require co-delivery of multiple nucleic acids. Therefore, the availability of reliable and robust co-transfection methods and defined selection criteria for their use in, e.g., expression of multimeric proteins or mixed RNA/DNA delivery is of utmost importance. Here, we investigated different co- and successive transfection approaches, with particular focus on in vitro transcribed messenger RNA (IVT-mRNA). Expression levels and patterns of two fluorescent protein reporters were determined, using different IVT-mRNA doses, carriers, and cell types. Quantitative parameters determining the efficiency of co-delivery were analyzed for IVT-mRNAs premixed before nanocarrier formation (integrated co-transfection) and when simultaneously transfecting cells with separately formed nanocarriers (parallel co-transfection), which resulted in a much higher level of expression heterogeneity for the two reporters. Successive delivery of mRNA revealed a lower transfection efficiency in the second transfection round. All these differences proved to be more pronounced for low mRNA doses. Concurrent delivery of siRNA with mRNA also indicated the highest co-transfection efficiency for integrated method. However, the maximum efficacy was shown for successive delivery, due to the kinetically different peak output for the two discretely operating entities. Our findings provide guidance for selection of the co-delivery method best suited to accommodate experimental requirements, highlighting in particular the nucleic acid dose-response dependence on co-delivery on the single-cell level.

Glaciated high-alpine areas are fundamentally altered by climate change, with well-known implications for hydrology, e.g., due to glacier retreat, longer snow-free periods, and more frequent and intense summer rainstorms. While knowledge on how these hydrological changes will propagate to suspended sediment dynamics is still scarce, it is needed to inform mitigation and adaptation strategies. To understand the processes and source areas most relevant to sediment dynamics, we analyzed discharge and sediment dynamics in high temporal resolution as well as their patterns on several spatial scales, which to date few studies have done. We used a nested catchment setup in the Upper Ötztal in Tyrol, Austria, where high-resolution (15 min) time series of discharge and suspended sediment concentrations are available for up to 15 years (2006–2020). The catchments of the gauges in Vent, Sölden and Tumpen range from 100 to almost 800 km2 with 10 % to 30 % glacier cover and span an elevation range of 930 to 3772 m a.s.l. We analyzed discharge and suspended sediment yields (SSY), their distribution in space, their seasonality and spatial differences therein, and the relative importance of short-term events. We complemented our analysis by linking the observations to satellite-based snow cover maps, glacier inventories, mass balances and precipitation data. Our results indicate that the areas above 2500 m a.s.l., characterized by glacier tongues and the most recently deglaciated areas, are crucial for sediment generation in all sub-catchments. This notion is supported by the synchronous spring onset of sediment export at the three gauges, which coincides with snowmelt above 2500 m but lags behind spring discharge onsets. This points at a limitation of suspended sediment supply as long as the areas above 2500 m are snow-covered. The positive correlation of annual SSY with glacier cover (among catchments) and glacier mass balances (within a catchment) further supports the importance of the glacier-dominated areas. The analysis of short-term events showed that summer precipitation events were associated with peak sediment concentrations and yields but on average accounted for only 21 % of the annual SSY in the headwaters. These results indicate that under current conditions, thermally induced sediment export (through snow and glacier melt) is dominant in the study area. Our results extend the scientific knowledge on current hydro-sedimentological conditions in glaciated high-alpine areas and provide a baseline for studies on projected future changes in hydro-sedimentological system dynamics.

The paper introduces the principle Maximise Presupposition and its cognates. The main focus of the literature and this article is on the inferences that arise as a result of reasoning with Maximise Presupposition ('anti-presuppositions'). I will review the arguments put forward for distinguishing them from other inference types, most notably presuppositions and conversational implicatures. I will zoom in on three main issues regarding Maximise Presupposition and these inferences critically discussed in the literature: epistemic strength(ening), projection, and the role of alternatives. I will discuss more recent views which argue for either a uniform treatment of anti-presuppositions and implicatures and/or a revision of the original principle in light of new data and developments in pragmatics.

Business model (BM) visualisations have become popular instruments with which to explain and manage today's complex business interactions. Using verbal and graphic elements, they provide simplified representations of reality and can support BM tasks that go beyond working memory's capacities. Visualisations thus reduce cognitive load and represent how practitioners and researchers think about BMs. However, they can also affect their thinking. This constitutes a thus far insufficiently explained tension between effectively reducing reality's complexity and the resulting cognitive biases. Building on cognitive load and framing theory, we qualitatively analysed 103 BM visualisations to explain how visual elements affect visualisations' cognitive effectiveness (helpfulness and ease of applicability) and unfold visual framing effects. By identifying five visual framing effects, we contribute to the cognitive BM perspective and explain how this set of cognitive factors affects BM management and research. We also found that most BM visualisations are not cognitively effective because they consist of unclear and non-parsimonious elements, limiting their cross-contextual application. Furthermore, the analysis revealed certain visualisations with strictly operationalised BM dimensions. These findings provide essential contributions to the literature on BM methods. We conclude by discussing how practitioners and researchers can use BM visualisations and their cognitive impacts accordingly.

Carbon dioxide removal from the atmosphere is becoming an important option to achieve net zero climate targets. This paper develops a welfare and public economics perspective on optimal policies for carbon removal and storage in non-permanent sinks like forests, soil, oceans, wood products or chemical products. We derive a new metric for the valuation of non-permanent carbon storage, the social cost of carbon removal (SCC-R), which embeds also the conventional social cost of carbon emissions. We show that the contribution of CDR is to create new carbon sinks that should be used to reduce transition costs, even if the stored carbon is released to the atmosphere eventually. Importantly, CDR does not raise the ambition of optimal temperature levels unless initial atmospheric carbon stocks are excessively high. For high initial atmospheric carbon stocks, CDR allows to reduce the optimal temperature below initial levels. Finally, we characterize three different policy regimes that ensure an optimal deployment of carbon removal: downstream carbon pricing, upstream carbon pricing, and carbon storage pricing. The policy regimes differ in their informational and institutional requirements regarding monitoring, liability and financing.

In the absence of a stranded auxiliary or modal, VP-topicalization in most Germanic languages gives rise to the presence of a dummy verb meaning 'do'. Cross-linguistically, this is a rather uncommon strategy as comparable VP-fronting constructions in other languages, e.g. Hebrew, Polish, and Portuguese, among many others, exhibit verb doubling. A comparison of several recent approaches to verb doubling in VP-fronting reveals that it is the consequence of VP-evacuating head movement of the verb to some higher functional head, which saves the (low copy of the) verb from undergoing copy deletion as part of the low VP copy in the VP-topicalization dependency. Given that almost all Germanic languages have such V-salvaging head movement, namely V-to-C movement, but do not show verb doubling, this paper suggests that V-raising is exceptionally impossible in VP-topicalization clauses and addresses the question of why it is blocked. After discussing and rejecting some conceivable explanations for the lack of verb doubling, I propose that the blocking effect arises from a bleeding interaction between V-to-C movement and VP-to-SpecCP movement. As both operations are triggered by the same head, i.e. C, the VP is always encountered first by a downward search algorithm. Movement of VP then freezes it and its lower copies for subextraction precluding subsequent V-raising. Crucially, this implies that there is no V-to-T raising in most Germanic languages. V2 languages with V-to-T raising, e.g. Yiddish, are correctly predicted to not exhibit the blocking effect.

A convenient method for the synthesis of gamma-spirolactams in only three steps is described. Birch reduction of inexpensive and commercially available aromatic carboxylic acids in the presence of chloroacetonitrile affords nitriles in moderate to good yields. Suitable precursors are methyl-substituted benzoic acids, naphthoic, and anthroic acid. Subsequent catalytic hydrogenation proceeds smoothly with PtO2 or Raney Ni as catalysts and lactams are isolated in excellent yields and stereoselectivities. Thus, up to 3 new stereogenic centers can be constructed as sole diastereomers from achiral benzoic acids. Furthermore, it is possible to control the degree of saturation at different pressures, affording products with 0, 1, or 2 double bonds. Overall, more than 15 new gamma-spirolactams have been synthesized in analytically pure form.

Earthquakes often rupture across more than one fault segment. If such rupture segmentation occurs on a significant scale, a simple point-source or one-fault model may not represent the rupture process well. As a consequence earthquake characteristics inferred, based on one-source assumptions, may become systematically wrong. This might have effects on follow-up analyses, for example regional stress field inversions and seismic hazard assessments. While rupture segmentation is evident for most M-w > 7 earthquakes, also smaller ones with 5.5 < M-w < 7 can be segmented. We investigate the sensitivity of globally available data sets to rupture segmentation and their resolution to reliably estimate the mechanisms in presence of segmentation. We focus on the sensitivity of InSAR (Interferometric Synthetic Aperture Radar) data in the static near-field and seismic waveforms in the far-field of the rupture and carry out non-linear and Bayesian optimizations of single-source and two-sources kinematic models (double-couple point sources and finite, rectangular sources) using InSAR and teleseismic waveforms separately. Our case studies comprises of four M-w 6-7 earthquakes: the 2009 L'Aquila and 2016 Amatrice (Italy) and the 2005 and 2008 Zhongba (Tibet) earthquakes. We contrast the data misfits of different source complexity by using the Akaike informational criterion (AIC). We find that the AIC method is well suited for data-driven inferences on significant rupture segmentation for the given data sets. This is based on our observation that an AIC-stated significant improvement of data fit for two-segment models over one-segment models correlates with significantly different mechanisms of the two source segments and their average compared to the single-segment mechanism. We attribute these modelled differences to a sufficient sensitivity of the data to resolve rupture segmentation. Our results show that near-field data are generally more sensitive to rupture segmentation of shallow earthquakes than far-field data but that also teleseismic data can resolve rupture segmentation in the studied magnitude range. We further conclude that a significant difference in the modelled source mechanisms for different segmentations shows that an appropriate choice of model segmentation matters for a robust estimation of source mechanisms. It reduces systematic biases and trade-off and thereby improves the knowledge on the rupture. Our study presents a strategy and method to detect significant rupture segmentation such that an appropriate model complexity can be used in the source mechanism inference. A similar, systematic investigation of earthquakes in the range of M-w 5.5-7 could provide important hazard-relevant statistics on rupture segmentation. In these cases single-source models introduce a systematic bias. Consideration of rupture segmentation therefore matters for a robust estimation of source mechanisms of the studied earthquakes.

This mixed-method study addresses the need for a clear conceptualization of the professional reflection element of Lesson Study (LS), a popular collaborative approach to the professional development of teachers. Grounding and re-framing LS's post-lesson discussion in a theoretical framework of critical and collaborative reflection, we analyze the transcripts of four LS groups at German primary schools, focusing on depth of reflection and teachers' trajectories through their reflective practice. The findings show that LS groups differed significantly in the depth and the trajectories of their reflection processes. We consider implications for post-lesson discussions and critical reflection as a LS core skill.

Observational studies are an important tool for determining whether the findings from controlled experiments can be transferred into scenarios that are closer to subjects' real-life circumstances. A rigorous approach to observational studies involves collecting data from different sensors to comprehensively capture the situation of the subject. However, this leads to technical difficulties especially if the sensors are from different manufacturers, as multiple data collection tools have to run simultaneously. We present SensorHub, a system that can collect data from various wearable devices from different manufacturers, such as inertial measurement units, portable electrocardiographs, portable electroencephalographs, portable photoplethysmographs, and sensors for electrodermal activity. Additionally, our tool offers the possibility to include ecological momentary assessments (EMAs) in studies. Hence, SensorHub enables multimodal sensor data collection under real-world conditions and allows direct user feedback to be collected through questionnaires, enabling studies at home. In a first study with 11 participants, we successfully used SensorHub to record multiple signals with different devices and collected additional information with the help of EMAs. In addition, we evaluated SensorHub's technical capabilities in several trials with up to 21 participants recording simultaneously using multiple sensors with sampling frequencies as high as 1000 Hz. We could show that although there is a theoretical limitation to the transmissible data rate, in practice this limitation is not an issue and data loss is rare. We conclude that with modern communication protocols and with the increasingly powerful smartphones and wearables, a system like our SensorHub establishes an interoperability framework to adequately combine consumer-grade sensing hardware which enables observational studies in real life.

Background: The LumiraDx INR Test is a new point-of-care diagnostic test designed to analyze fingerstick blood samples. The test was assessed in patients receiving phenprocoumon (NCT04074980). Methods: Venous plasma international normalized ratio (INR) was measured using the LumiraDx INR Test. LumiraDx INR Test-ascertained capillary whole blood INR was compared with venous plasma INR measured using the IL ACL Elite Pro and Sysmex CS-5100 reference instruments. Results: A total of 102 patients receiving phenprocoumon were recruited. The INR results from venous plasma and capillary whole blood that were analyzed on the LumiraDx INR Test correlated well with those measured using the IL ACL Elite Pro (plasma: n = 25, r = 0.981; capillary blood: n = 74, r = 0.949) and the Sysmex CS-5100 (n = 73, r = 0.950). Conclusions: The LumiraDx INR Test showed high accuracy in analyzing venous plasma and capillary whole blood from patients receiving phenprocoumon.

Mammalian arachidonic acid lipoxygenases (ALOXs) have been implicated in cell differentiation and in the pathogenesis of inflammation. The mouse genome involves seven functional Alox genes and the encoded enzymes share a high degree of amino acid conservation with their human orthologs. There are, however, functional differences between mouse and human ALOX orthologs. Human ALOX15B oxygenates arachidonic acid exclusively to its 15-hydroperoxy derivative (15S-HpETE), whereas 8S-HpETE is dominantly formed by mouse Alox15b. The structural basis for this functional difference has been explored and in vitro mutagenesis humanized the reaction specificity of the mouse enzyme. To explore whether this mutagenesis strategy may also humanize the reaction specificity of mouse Alox15b in vivo, we created Alox15b knock-in mice expressing the arachidonic acid 15-lipoxygenating Tyr603Asp+His604Val double mutant instead of the 8-lipoxygenating wildtype enzyme. These mice are fertile, display slightly modified plasma oxylipidomes and develop normally up to an age of 24 weeks. At later developmental stages, male Alox15b-KI mice gain significantly less body weight than outbred wildtype controls, but this effect was not observed for female individuals. To explore the possible reasons for the observed gender-specific growth arrest, we determined the basic hematological parameters and found that aged male Alox15b-KI mice exhibited significantly attenuated red blood cell parameters (erythrocyte counts, hematocrit, hemoglobin). Here again, these differences were not observed in female individuals. These data suggest that humanization of the reaction specificity of mouse Alox15b impairs the functionality of the hematopoietic system in males, which is paralleled by a premature growth arrest.

Die aktuelle COVID-19-Pandemie zeigt deutlich, wie sich Infektionskrankheiten weltweit verbreiten können. Neben Viruserkrankungen breiten sich auch multiresistente bakterielle Erreger weltweit aus. Dementsprechend besteht ein hoher Bedarf, durch frühzeitige Erkennung Erkrankte zu finden und Infektionswege zu unterbrechen. Herkömmliche kulturelle Verfahren benötigen minimalinvasive bzw. invasive Proben und dauern für Screeningmaßnahmen zu lange. Deshalb werden schnelle, nichtinvasive Verfahren benötigt. Im klassischen Griechenland verließen sich die Ärzte unter anderem auf ihren Geruchssinn, um Infektionen und andere Krankheiten zu differenzieren. Diese charakteristischen Gerüche sind flüchtige organische Substanzen (VOC), die im Rahmen des Metabolismus eines Organismus entstehen. Tiere, die einen besseren Geruchssinn haben, werden trainiert, bestimmte Krankheitserreger am Geruch zu unterscheiden. Allerdings ist der Einsatz von Tieren im klinischen Alltag nicht praktikabel. Es bietet sich an, auf technischem Weg diese VOCs zu analysieren. Ein technisches Verfahren, diese VOCs zu unterscheiden, ist die Ionenmobilitätsspektrometrie gekoppelt mit einer multikapillaren Gaschromatographiesäule (MCC-IMS). Hier zeigte sich, dass es sich bei dem Verfahren um eine schnelle, sensitive und verlässliche Methode handelt. Es ist bekannt, dass verschiedene Bakterien aufgrund des Metabolismus unterschiedliche VOCs und damit eigene spezifische Gerüche produzieren. Im ersten Schritt dieser Arbeit konnte gezeigt werden, dass die verschiedenen Bakterien in-vitro nach einer kurzen Inkubationszeitzeit von 90 Minuten anhand der VOCs differenziert werden können. Hier konnte analog zur Diagnose in biochemischen Testreihen eine hierarchische Klassifikation der Bakterien erfolgen. Im Gegensatz zu Bakterien haben Viren keinen eigenen Stoffwechsel. Ob virusinfizierte Zellen andere VOCs als nicht-infizierte Zellen freisetzen, wurde an Zellkulturen überprüft. Hier konnte gezeigt werden, dass sich die Fingerprints der VOCs in Zellkulturen infizierter Zellen mit Respiratorischen Synzytial-Viren (RSV) von nicht-infizierten Zellen unterscheiden. Virusinfektionen im intakten Organismus unterscheiden sich von den Zellkulturen dadurch, dass hier neben Veränderungen im Zellstoffwechsel auch durch Abwehrmechanismen VOCs freigesetzt werden können. Zur Überprüfung, inwiefern sich Infektionen im intakten Organismus ebenfalls anhand VOCs unterscheiden lassen, wurde bei Patienten mit und ohne Nachweis einer Influenza A Infektion als auch bei Patienten mit Verdacht auf SARS-CoV-2 (Schweres-akutes-Atemwegssyndrom-Coronavirus Typ 2) Infektion die Atemluft untersucht. Sowohl Influenza-infizierte als auch SARS-CoV-2 infizierte Patienten konnten untereinander und von nicht-infizierten Patienten mittels MCC-IMS Analyse der Atemluft unterschieden werden. Zusammenfassend erbringt die MCC-IMS ermutigende Resultate in der schnellen nichtinvasiven Erkennung von Infektionen sowohl in vitro als auch in vivo.

Mehr als vier Jahrzehnte lang beobachteten die Streitkräfte und Militärnachrichtendienste der NATO-Staaten die sowjetischen Truppen in der DDRD. Hierfür übernahm in der Bundesrepublik Deutschland der Bundesnachrichtendienst (BND) die militärische Auslandsaufklärung unter Anwendung nachrichtendienstlicher Mittel und Methoden. Die Bundeswehr betrieb dagegen taktische Fernmelde- und elektronische Aufklärung und hörte vor allem den Funkverkehr der „Gruppe der sowjetischen Streitkräfte in Deutschland“ (GSSD) ab. Mit der Aufstellung einer zentralen Dienststelle für das militärische Nachrichtenwesen, dem Amt für Nachrichtenwesen der Bundeswehr, bündelte und erweiterte zugleich das Bundesministerium für Verteidigung in den 1980er Jahren seine analytischen Kapazitäten. Das Monopol des BND in der militärischen Auslandsaufklärung wurde von der Bundeswehr dadurch zunehmend infrage gestellt. Nach der deutschen Wiedervereinigung am 3. Oktober 1990 befanden sich immer noch mehr als 300.000 sowjetische Soldaten auf deutschem Territorium. Die 1989 in Westgruppe der Truppen (WGT) umbenannte GSSD sollte – so der Zwei-plus-Vier-Vertrag – bis 1994 vollständig abziehen. Der Vertrag verbot auch den drei Westmächten, in den neuen Bundesländern militärisch tätig zu sein. Die für die Militäraufklärung bis dahin unverzichtbaren Militärverbindungsmissionen der Westmächte mussten ihre Dienste einstellen. Doch was geschah mit diesem „alliierten Erbe“? Wer übernahm auf deutscher Seite die Aufklärung der sowjetischen Truppen und wer kontrollierte den Truppenabzug?  Die Studie untersucht die Rolle von Bundeswehr und BND beim Abzug der WGT zwischen 1990 und 1994 und fragt dabei nach Kooperation und Konkurrenz zwischen Streitkräften und Nachrichtendiensten. Welche militärischen und nachrichtendienstlichen Mittel und Fähigkeiten stellte die Bundesregierung zur Bewältigung des Truppenabzugs zur Verfügung, nachdem die westlichen Militärverbindungsmissionen aufgelöst wurden? Wie veränderten sich die Anforderungen an die militärische Auslandsaufklärung des BND? Inwieweit setzten sich Konkurrenz und Kooperation von Bundeswehr und BNDbeim Truppenabzug fort? Welche Rolle spielten dabei die einstigen Westmächte? Die Arbeit versteht sich nicht nur als Beitrag zur Militärgeschichte, sondern auch zur deutschen Nachrichtendienstgeschichte.

Cyber-physical systems often encompass complex concurrent behavior with timing constraints and probabilistic failures on demand. The analysis whether such systems with probabilistic timed behavior adhere to a given specification is essential. When the states of the system can be represented by graphs, the rule-based formalism of Probabilistic Timed Graph Transformation Systems (PTGTSs) can be used to suitably capture structure dynamics as well as probabilistic and timed behavior of the system. The model checking support for PTGTSs w.r.t. properties specified using Probabilistic Timed Computation Tree Logic (PTCTL) has been already presented. Moreover, for timed graph-based runtime monitoring, Metric Temporal Graph Logic (MTGL) has been developed for stating metric temporal properties on identified subgraphs and their structural changes over time. In this paper, we (a) extend MTGL to the Probabilistic Metric Temporal Graph Logic (PMTGL) by allowing for the specification of probabilistic properties, (b) adapt our MTGL satisfaction checking approach to PTGTSs, and (c) combine the approaches for PTCTL model checking and MTGL satisfaction checking to obtain a Bounded Model Checking (BMC) approach for PMTGL. In our evaluation, we apply an implementation of our BMC approach in AutoGraph to a running example.