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Earth Observations (EO) have become crucial for advancing climate and Earth System research, enabling significant scientific discoveries. Advanced EO missions, such as ESA’s Earth Explorers and the EU's Copernicus Programme, provide vast data volumes and continuous and global observations with cutting-edge technology, a vital resource for understanding processes and interactions within Earth's sub-systems, offering critical evidence of climate change impacts on society and ecosystems. Open access to such data products has been instrumental in facilitating global scientific collaboration and innovation. Reproducibility in Earth Science is essential for validating discoveries, enabling the scientific community to trust and build upon each other’s work. Open data, coupled with open-source software, is key to achieving this reproducibility, ensuring transparency, and facilitating peer review. Addressing scientific challenges requires collaborative efforts supported by fit-for-purpose technology to enable new insights and ensuring they are FAIR (findable, accessible, interoperable, and reusable), trustable and up to date, supporting long-term climate studies and action-driven science. Several initiatives within ESA’s Earth Observation Programme are fostering FAIR and Open Science. EarthCODE is one such initiative, focusing on implementing ESA’s vision of EO Open Science and Innovation by adopting FAIR and Open principles in Earth Science activities funded by ESA’s FutureEO Programme. EarthCODE leverages existing European platform solutions for effective cloud-based analyses of EO data and higher-level geospatial products. It aims to ensure the persistence of end-to-end scientific workflows and provide means for managing open research data, including data, code, and documentation. EarthCODE aims to make Earth Science research more reproducible, transparent, and collaborative, driving progress in understanding and addressing global environmental challenges.

The Deep Earth System Data Lab (DeepESDL) provides an AI-ready, collaborative environment for researchers aiming to study the Earth's complex dynamics using various datasets and empirical approaches. Recently opened to Early Adopters, it builds on projects like CAB-LAB and ESDL, utilizing well-established Python and Julia technology stacks. DeepESDL offers programmatic access to extensive analysis-ready data cubes and computational resources, enabling researchers to focus on analysis without extensive preparations. Scientists can use persistently available data cubes or generate user-tailored cubes from own data or publicly available datasets. The goal is to streamline data processing through empirical or AI methods within high-dimensional Earth Observation workflows. DeepESDL addresses the complete research cycle, from discovery of earth data to powerful analyses, collaborative scientific research, advanced data visualisation and publication of results, promoting FAIR and Open Science. Apart from serving as a research environment, DeepESDL showcases scientific use cases and supports educational purposes through capacity building, academic programs, and Open Science initiatives. This paper presents an overview of DeepESDL.

The "Cubes and Clouds" Massive Open Online Course (MOOC) addresses the growing challenges and opportunities in Earth Observation (EO) data analysis posed by the exponential growth of satellite missions and data volumes. This course introduces cloud-native EO concepts and open science principles, facilitating collaboration and data sharing within the EO community.Key topics covered in the MOOC include data discovery, processing workflows, and data sharing using real-world examples like snow cover mapping in the Alps. Participants engage with interactive lessons, videos, and hands-on coding exercises, leveraging freely available geospatial data and emphasizing open data principles and interoperability.The course infrastructure seamlessly integrates with cloud platforms like the Copernicus Data Space Ecosystem, enabling learners to apply concepts in a practical, cloud-based environment. Initial user statistics indicate strong interest, particularly among early-career professionals and researchers, with participant surveys suggesting increased confidence in using EO cloud platforms and embracing open science practices upon course completion.Overall, "Cubes and Clouds" serves as a valuable resource for the EO community, fostering transparency, collaboration, and innovation in geospatial science. Future developments aim to expand course content and attract diverse user groups, ensuring broader accessibility and long-term impact in advancing cloud-native EO and open science initiatives.

Aims: Acute heart failure (AHF) is typified by inflammatory and oxidative stress responses, which are associated with unfavorable patient outcomes. Given the anti-inflammatory and antioxidant properties of high-density lipoprotein (HDL), this study sought to examine the relationship between impaired HDL function and mortality in AHF patients. The complex interplay between various HDL-related biomarkers and clinical outcomes remains poorly understood. Methods: HDL subclass distribution was quantified by nuclear magnetic resonance spectroscopy. Lecithin–cholesterol acyltransferase (LCAT) activity, cholesterol ester transfer protein (CETP) activity, and paraoxonase (PON-1) activity were assessed using fluorometric assays. HDL-cholesterol efflux capacity (CEC) was assessed in a validated assay using [3H]-cholesterol-labeled J774 macrophages. Results: Among the study participants, 74 (23.5 %) out of 315 died within three months after hospitalization due to AHF. These patients exhibited lower activities of the anti-oxidant enzymes PON1 and LCAT, impaired CEC, and lower concentration of small HDL subclasses, which remained significant after accounting for potential confounding factors. Smaller HDL particles, particularly HDL3 and HDL4, exhibited a strong association with CEC, PON1 activity, and LCAT activity. Conclusions: In patients with AHF, impaired HDL CEC, HDL antioxidant and anti-inflammatory function, and impaired HDL metabolism are associated with increased mortality. Assessment of HDL function and subclass distribution could provide valuable clinical information and help identify patients at high risk.

Open Science is a catalyst for innovation. Across the Earth Observation value chain, from R&D to prototyping new products and development of commercial applications, openness can play an important role by promoting long-term sustainable, community-contributed science and technology. The FAIR principles provide essential support to implementing Open Science, by offering guidelines for how researchers can adapt their EO and Earth Science practice to enable that their work (taking place increasingly in the cloud) and results are discovered, accessed, used, and reproduced by others. The Open Science Data Catalogue (OSC) (https://opensciencedata.esa.int) is an ESA Open Science activity aiming to enhance the discoverability and use of the various scientific and value-added results (i.e. data, code, documentation) achieved in Earth System Science research activities funded by ESA EO. The OSC provides open access for the scientific community to geoscience products (based on EO data from ESA and non-ESA missions and other geospatial information and models) across the whole spectrum of Earth Science domains. The OSC adheres to FAIR principles and promotes reproducibility of scientific studies. The OSC makes use of various Open-Source geospatial technologies such as pycsw, PySTAC, and OpenLayers and tries to contribute back to these projects in terms of software and standardisation. This paper reviews the EO OSC architecture, technology stack, and illustrates how this tool can be used to discover and publish Earth System Science products from ESA activities. It also looks at future evolutions of the product and how it contributes to ESA’s EO Open Science and Innovation goals.

Although research into multimodal stance-taking has gained momentum over the past years, the multimodal construction of so-called stacked stances has not yet received systematic attention in the literature. Mocking enactments are a prime example of such complex social actions as they are layered both interactionally and stance-related, and they rely significantly on the use of bodily visual resources, depicting rather than describing events and stances. Using Du Bois’ Stance Triangle as a framework, this study investigates mocking enactments as a case study to unravel the multimodal aspects of layered stance expressions. Drawing on three data sets—music instruction in Dutch, German, and English, spontaneous face-to-face interactions among friends in Dutch, and narrations on past events in Flemish Sign Language (VGT)—this study provides a qualitative exploration of mocking enactments across different communicative settings, languages, and modalities. The study achieves three main objectives: (1) illuminating how enactments are used for mocking, (2) identifying the layers of stance-taking at play, and (3) examining the multimodal construction of mocking enactments. Our analysis reveals various different uses of enactments for mocking. Aside from enacting the target of the mockery, participants can include other characters and viewpoints, highlighting the breadth of the phenomenon under scrutiny. Second, we uncover the layered construction of stance on all axes of the Stance Triangle (evaluation, positioning, and alignment). Third, we find that mocking enactments are embedded in highly evaluative contexts, indexed by the use of bodily visual resources. Interestingly, not all mocking enactments include a multimodally exaggerated depiction, but instead, some merely allude to an absurd hypothetical scenario. Our findings contribute to the growing body of literature on multimodal stance-taking, by showing how a nuanced interpretation of the Stance Triangle can offer a useful framework for analyzing layered stance acts.

In small Alpine catchments, floods are mostly triggered by surface runoff generation during convective heavy precipitation events. Their magnitude also depends on the antecedent soil moisture content, which was shown in several previous studies. This study aims at understanding (a) which sites change their surface runoff response to rainfall events with high precipitation intensity under very moist pre-conditions to what extent and (b) on which site characteristics this depends on. Therefore, we conducted repeated rainfall simulation experiments (40–80 m2, 1 h, 100 mm h−1) at 20 sites in five Eastern Alpine areas and analyzed their results on the basis of soil-physical parameters derived from collected soil samples.The hay meadow sites reacted with a strong increase in surface runoff to reduced saturation deficits, the pasture sites showed a smaller but visible response. The forest sites had the highest water retention capacities. The change in the surface runoff response is a function of the saturation deficit at the beginning of the initial experiment (r = −0.58). The soil physical parameters, especially the fine pore fraction (r = 0.56), correlate with the difference of the total surface runoff coefficient between the initial and the repeated experiment. The fine pore fraction also shows a high correlation (r = −0.78) with the saturation deficit at the beginning of the initial experiment, although pores of this fraction were saturated during all experiments. (Non-quantifiable) Land use effects, which in turn influence the soil physical parameters, play an important role in explaining how the surface runoff response in the repeated rainfall simulation experiment differs from the initial experiment. The information on land use and soil characteristics allowed the sites to be categorized into four types in terms of surface runoff disposition and the increase in total surface runoff coefficient in the second rainfall simulation experiment.

Stance-taking, the public act of positioning oneself toward objects, people or states of affairs, has been studied in many fields of research. Recently, its multimodal realization in interaction has received increasing attention. The current contribution aims to take stock of research on multimodal stance-taking so far, and to present possible avenues for future research. We systematically gathered and appraised 76 articles that investigate the involvement of bodily-visual resources in stance-taking in interaction. The critical appraisal focused on two dimensions of the stance act: form-function relations constituting it, and its dynamic organization in interaction. Regarding form-function relations, we found systematic involvement of specific bodily-visual resources in different stance acts, as well as patterns of multimodal intensification and mitigation of stances. As for its dynamic organization, the review discusses how stance-taking is organized temporally throughout an interaction, with all participants involved carefully negotiating and adapting their stances to one another. Finally, attention is paid to the broader context of stance-taking, including its role in different social and societal contexts. Based on this review, we were able to identify several gaps in the literature, and avenues for future research. We argue that much potential for broadening the scope of research lies in increasing the methodological diversity in approaching multimodal stance-taking, as well as in cross-linguistic studies and varying settings and participant constellations. In conclusion, research into multimodal stance-taking is vibrant, with ample opportunities for future work. This review can be considered as a call to action to move beyond the premise that stance-taking is multimodal, and further investigate this intriguing and fundamental human capacity.

COVID-19, caused by the SARS-CoV-2 coronavirus, emerged as a global pandemic in late 2019, resulting in significant global public health challenges. The emerging evidence suggests that diminished high-density lipoprotein (HDL) cholesterol levels are associated with the severity of COVID-19, beyond inflammation and oxidative stress. Here, we used nuclear magnetic resonance spectroscopy to compare the lipoprotein and metabolic profiles of COVID-19-infected patients with non-COVID-19 pneumonia. We compared the control group and the COVID-19 group using inflammatory markers to ensure that the differences in lipoprotein levels were due to COVID-19 infection. Our analyses revealed supramolecular phospholipid composite (SPC), phenylalanine, and HDL-related parameters as key discriminators between COVID-19-positive and non-COVID-19 pneumonia patients. More specifically, the levels of HDL parameters, including apolipoprotein A-I (ApoA-I), ApoA-II, HDL cholesterol, and HDL phospholipids, were significantly different. These findings underscore the potential impact of HDL-related factors in patients with COVID-19. Significantly, among the HDL-related metrics, the cholesterol efflux capacity (CEC) displayed the strongest negative association with COVID-19 mortality. CEC is a measure of how well HDL removes cholesterol from cells, which may affect the way SARS-CoV-2 enters cells. In summary, this study validates previously established markers of COVID-19 infection and further highlights the potential significance of HDL functionality in the context of COVID-19 mortality.

In this contribution, we examine the way in which orchestra conductors use the space around them to convey aspects of musical dynamics. In music, dynamics refers to the intensity of volume of notes and sounds and its interpretation is highly context-bound. We approach dynamics as a phenomenon of emergent and construed meaning in interaction, induced by the music score and the interpretation in situ by musicians and the conductor. Conductors' movement-based instructions on dynamics result in highly complex usage events. This study aims at disentangling these instances by asking how conductors move and use the space around them to instruct on (un)desired aspects of musical dynamics, zooming in on movement direction as a central formal feature. We find ourselves at the crossroads of cognitive and interactional linguistics, aligning with existing studies on the interactional and contextually embedded nature of music interaction. From a cognitive linguistic perspective, this endeavor translates as the identification of the construal mechanisms (metaphor, specificity and viewpoint) that underlie and therefore motivate movement directions in the specific instances under examination. The analysis is based on 10h of video data from a corpus recorded during rehearsals of five conductors instructing their respective orchestras in Dutch. Our data reveal that conductors use different movement patterns, some of which appear to involve opposite movement directions for expressing a similar music dynamical aspect, e.g., depending on the usage event, a vertical upward movement can mean both a request for playing louder and softer. By taking into account different construal mechanisms, we are able to provide an encompassing multimodal analysis, in which these allegedly deviating oppositional movements appear as consistently motivated (metaphorical) expressions, which profile a similar target concept involving different viewpoints.

Abstract Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory biomarker and risk factor for kidney diseases, with a potential prognostic value in critically ill patients. In this monocentric prospective study, we measured plasma suPAR levels immediately after ICU admission in unselected 237 consecutive patients using a turbidimetric assay. Primary objective was the prognostic value for ICU- and 28-day mortality. Secondary objectives were association with sequential organ failure assessment (SOFA) score, coagulation and inflammation markers, AKI-3 and differences in prespecified subgroups. Median suPAR levels were 8.0 ng/mL [25th-75th percentile 4.3–14.4], with lower levels in ICU survivors than non-survivors (6.7 vs. 11.6 ng/mL, p 7, SOFA ≤ 7 & suPAR > 8 ng/mL, and SOFA score ≤ 7 & suPAR ≤ 8 ng/mL, respectively. suPAR was a significant predictor for AKI-3 occurrence (OR per doubling 1.89, 95% CI: 1.20–2.98; p = 0.006). suPAR levels at ICU admission may offer additional value for risk stratification especially in ICU patients with moderate organ dysfunction as reflected by a SOFA score ≤ 7.

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase/signal transducer and activator of transcription pathway, which is central in cytokine signaling. Previously, germline TYK2 mutations have been described in two patients developing de novo T-cell acute lymphoblastic leukemias (T-ALL) or precursor B-ALL. The mutations (P760L and G761V) are located within the regulatory pseudokinase domain and lead to constitutive activation of TYK2. We demonstrate the transformation capacity of TYK2 P760L in hematopoietic cell systems including primary bone marrow cells. In vivo engraftment of TYK2 P760L-expressing cell lines led to development of leukemia. A kinase inhibitor screen uncovered that oncogenic TYK2 acts synergistically with the PI3K/AKT/mTOR and CDK4/6 pathways. Accordingly, the TYK2-specific inhibitor deucravacitinib (BMS986165) reduces cell viability of TYK2 P760L-transformed cell models and ex vivo cultured TYK2 P760L-mutated patient- derived xenograft cells most efficiently when combined with mTOR or CDK4/6 inhibitors. Our study thereby pioneers novel treatment options for patients suffering from TYK2-driven acute leukemia.

Innate lymphoid cells (ILC) play a significant role in the intestinal immune response and T-bet+ CD127+ group 1 cells (ILC1) have been linked to the pathogenesis of human inflammatory bowel disease (IBD). However, the functional importance of ILC1 in the context of an intact adaptive immune response has been controversial. In this report we demonstrate that induced depletion of T-bet using a Rosa26-Cre-ERT2 model resulted in the loss of intestinal ILC1, pointing to a post-developmental requirement of T-bet expression for these cells. In contrast, neither colonic lamina propria (cLP) ILC2 nor cLP ILC3 abundance were altered upon induced deletion of T-bet. Mechanistically, we report that STAT1 or STAT4 are not required for intestinal ILC1 development and maintenance. Mice with induced deletion of T-bet and subsequent loss of ILC1 were protected from the induction of severe colitis in vivo. Hence, this study provides support for the clinical development of an IBD treatment based on ILC1 depletion via targeting T-bet or its downstream transcriptional targets.

This article presents and analyses the modular architecture and capabilities of CODE-DE (Copernicus Data and Exploitation Platform – Deutschland, www.code-de.org), the integrated German operational environment for accessing and processing Copernicus data and products, as well as the methodology to establish and operate the system. Since March 2017, CODE-DE has been online with access to Sentinel-1 and Sentinel-2 data, to Sentinel-3 data shortly after this time, and since March 2019 with access to Sentinel-5P data. These products are available and accessed by 1,682 registered users as of March 2019. During this period 654,895 products were downloaded and a global catalogue was continuously updated, featuring a data volume of 814 TByte based on a rolling archive concept supported by a reload mechanism from a long-term archive. Since November 2017, the element for big data processing has been operational, where registered users can process and analyse data themselves specifically assisted by methods for value-added product generation. Utilizing 195,467 core and 696,406 memory hours, 982,948 products of different applications were fully automatically generated in the cloud environment and made available as of March 2019. Special features include an improved visualization of available Sentinel-2 products, which are presented within the catalogue client at full 10 m resolution.

Innate lymphoid cells (ILC) play a significant immunological role at mucosal surfaces such as the intestine. T-bet-expressing group 1 innate lymphoid cells (ILC1) are believed to play a substantial role in inflammatory bowel disease (IBD). However, a role of T-bet-negative ILC3 in driving colitis has also been suggested in mouse models questioning T-bet as a critical factor for IBD. We report here that T-bet deficient mice had a greater cellularity of NKp46-negative ILC3 correlating with enhanced expression of RORγt and IL-7R, but independent of signaling through STAT1 or STAT4. We observed enhanced neutrophilia in the colonic lamina propria (cLP) of these animals, however, we did not detect a greater risk of T-bet-deficient mice to develop spontaneous colitis. Furthermore, by utilizing an in vivo fate-mapping approach, we identified a population of T-bet-positive precursors in NKp46-negative ILC3s. These data suggest that T-bet controls ILC3 cellularity, but does do not drive a pathogenic role of ILC3 in mice with a conventional specific pathogen-free microbiota.

Natural killer (NK) cells are important components of the innate immune defense against infections and cancers. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that is essential for NK cell maturation and NK cell-dependent tumor surveillance. Two alternatively spliced isoforms of STAT1 exist: a full-length STAT1α and a C-terminally truncated STAT1β isoform. Aberrant splicing is frequently observed in cancer cells and several anti-cancer drugs interfere with the cellular splicing machinery. To investigate whether NK cell-mediated tumor surveillance is affected by a switch in STAT1 splicing, we made use of knock-in mice expressing either only the STAT1α (Stat1α/α) or the STAT1β (Stat1β/β) isoform. NK cells from Stat1α/α mice matured normally and controlled transplanted tumor cells as efficiently as NK cells from wild-type mice. In contrast, NK cells from Stat1β/β mice showed impaired maturation and effector functions, albeit less severe than NK cells from mice that completely lack STAT1 (Stat1–/–). Mechanistically, we show that NK cell maturation requires the presence of STAT1α in the niche rather than in NK cells themselves and that NK cell maturation depends on IFNγ signaling under homeostatic conditions. The impaired NK cell maturation in Stat1β/β mice was paralleled by decreased IL-15 receptor alpha (IL-15Rα) surface levels on dendritic cells, macrophages and monocytes. Treatment of Stat1β/β mice with exogenous IL-15/IL-15Rα complexes rescued NK cell maturation but not their effector functions. Collectively, our findings provide evidence that STAT1 isoforms are not functionally redundant in regulating NK cell activity and that the absence of STAT1α severely impairs, but does not abolish, NK cell-dependent tumor surveillance.

Study region: Brixenbach catchment (10 km²), Kitzbuehel Alps, Tyrol, Austria. Study focus: This study presents the data of one of the rare soil moisture networks in the Alps, a 9-year soil moisture time series recorded at 8 sites with in-situ measurements (six pasture and two forest sites). We aim at understanding the soil moisture behaviour in general, its reaction to rainfall considering the site characteristics and the runoff reaction depending on the antecedent soil moisture content. We analysed soil moisture, rainfall and discharge data with a temporal resolution of one hour (summer months) and two hours (autumn to spring) respectively and interpreted the results in terms of land use and topographical features. New hydrological insights for the region: The medians of the soil moisture positively correlate with the sites’ altitude. Comparing spatial standard deviation of soil moisture versus spatial mean shows a high scatter of the standard deviations, contrary to previous studies, which use considerably shorter time series. The spatial variability increases with spatial mean, thus the highest spatial variability is recorded at wet conditions. The catchment shows clear threshold behaviour: Runoff coefficients above 0.23 only occurred when the soil moisture spatial mean of the eight sites overrun 43.5 vol% which can be translated into a saturation deficit of 0.28.

CVD remains the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). CKD profoundly affects HDL composition and functionality, but whether abnormal HDL independently contributes to cardiovascular events in CKD patients remains elusive. In the present study, we assessed whether compositional and functional properties of HDL predict cardiovascular outcome among 526 nondialysis CKD patients who participate in the CARE FOR HOMe study. We measured HDL cholesterol, the content of HDL-associated proinflammatory serum amyloid A (SAA), and activities of the HDL enzymes paraoxonase and lipoprotein-associated phospholipase A2 (Lp-PLA2). In addition, we assessed the antioxidative activity of apoB-depleted serum. During a mean follow-up of 5.1 ± 2.1 years, 153 patients reached the predefined primary endpoint, a composite of atherosclerotic cardiovascular events including cardiovascular mortality and death of any cause. In univariate Cox regression analyses, lower HDL-cholesterol levels, higher HDL-associated SAA content, and lower paraoxonase activity predicted cardiovascular outcome, while Lp-PLA2 activity and antioxidative capacity did not. HDL-cholesterol and HDL-paraoxonase activity lost their association with cardiovascular outcome after adjustment for traditional cardiovascular and renal risk factors, while SAA lost its association after further adjustment for C-reactive protein. In conclusion, our data suggest that neither HDL quantity nor HDL composition or function independently predict cardiovascular outcome among nondialysis CKD patients.

STAT1 has a key role in the regulation of innate and adaptive immunity by inducing transcriptional changes in response to cytokines, such as all types of interferons (IFN). STAT1 exist as two splice isoforms, which differ in regard to the C-terminal transactivation domain (TAD). STAT1β lacks the C-terminal TAD and has been previously reported to be a weaker transcriptional activator than STAT1α, although this was strongly dependent on the target gene. The mechanism of this context-dependent effects remained unclear. By using macrophages from mice that only express STAT1β, we investigated the role of the C-terminal TAD during the distinct steps of transcriptional activation of selected target genes in response to IFNγ. We show that the STAT1 C-terminal TAD is absolutely required for the recruitment of RNA polymerase II (Pol II) and for the establishment of active histone marks at the class II major histocompatibility complex transactivator (CIIta) promoter IV, whereas it is dispensable for histone acetylation at the guanylate binding protein 2 (Gbp2) promoter but required for an efficient recruitment of Pol II, which correlated with a strongly reduced, but not absent, transcriptional activity. IFNγ-induced expression of Irf7, which is mediated by STAT1 in complex with STAT2 and IRF9, did not rely on the presence of the C-terminal TAD of STAT1. Moreover, we show for the first time that the STAT1 C-terminal TAD is required for an efficient recruitment of components of the core Mediator complex to the IFN regulatory factor (Irf) 1 and Irf8 promoters, which both harbor an open chromatin state under basal conditions. Our study identified novel functions of the STAT1 C-terminal TAD in transcriptional activation and provides mechanistic explanations for the gene-specific transcriptional activity of STAT1β.

Motivated by tunnel accidents in the recent past, several investigations into the sustained load behavior of adhesive anchors have been initiated. Nevertheless, the reliable lifetime prediction of bonded anchor systems based on a relatively short testing period still represents an unsolved challenge due to the complex nonlinear viscoelastic behavior of concrete and adhesives alike. This contribution summarizes the results of a comprehensive experimental investigation and systematically carried out time-to-failure analysis performed on bonded anchors under sustained tensile load. Two different adhesive materials that find widespread application in the building industry were used, one epoxy and one vinylester based. Performed experiments include full material characterizations of concrete and the adhesives, bonded anchor pull-out tests at different loading rates, and time-to-failure sustained load tests. All anchor tests are performed in a confined configuration with close support. After a thorough review of available experimental data and analysis methods in the literature, the experimental data are presented with the main goal to (i) provide guidance for the analysis of load versus time-to-failure test data, and (ii) to derive a set of recommendations for efficient time-to-failure tests having in mind the needs associated with different analysis techniques. Finally, a new approach based on a sigmoid function, previously used only for concrete, is for the first time applied to bonded anchors systems and compared to the established regression models.

Tyrosine kinase 2 (TYK2) is a Janus kinase (JAK) that is crucially involved in inflammation, carcinogenesis and defense against infection. The cytotoxic activity of natural killer (NK) cells in TYK2-deficient (Tyk2−/−) mice is severely reduced, although the underlying mechanisms are largely unknown. Using Tyk2−/− mice and mice expressing a kinase-inactive version of TYK2 (Tyk2K923E), we show that NK cell function is partly independent of the enzymatic activity of TYK2. Tyk2−/− and Tyk2K923E NK cells develop normally in the bone marrow, but the maturation of splenic Tyk2−/− NK cells (and to a lesser extent of Tyk2K923E NK cells) is impaired. In contrast, the production of interferon γ (IFNγ) in response to interleukin 12 (IL-12) or to stimulation through NK cell-activating receptors strictly depends on the presence of enzymatically active TYK2. The cytotoxic activity of Tyk2K923E NK cells against a range of target cells in vitro is higher than that of Tyk2−/− NK cells. Consistently, Tyk2K923E mice control the growth of NK cell-targeted tumors significantly better than TYK2-deficient mice, showing the physiological relevance of the finding. Inhibitors of TYK2's kinase activity are being developed for the treatment of inflammatory diseases and cancers, but their effects on tumor immune surveillance have not been investigated. Our finding that TYK2 has kinase-independent functions in vivo suggests that such inhibitors will leave NK cell mediated tumor surveillance largely intact and that they will be suitable for use in cancer therapy.

While science widely acknowledges the necessity of climate change adaptation (CCA), concrete strategies for CCA by major land-use actor groups at a local level are largely missing. Immediate economic challenges often prevent the establishment of long-term collective strategies. However, collective decisions on a communal level regarding land use are crucial for CCA strategies, given the interdependencies of farming with forestry, tourism, and other economic sectors, especially in mountain areas. This paper presents inter- and trans-disciplinary learning processes, which have evolved into a project modelling the hydrological effects of combined future climate and land-use changes based on the combined scenarios of climate and socio-economic change in an Alpine valley (Brixental in Tyrol/Austria). Locally adapted scenarios illustrate future land-use changes as a result of both climate change and different socio-economic developments. The hydrological results show how an increase in the forested area reduces streamflow (as a measure of water availability) in the long term. For local stakeholders, the process demonstrated clearly the interdependence of different economic sectors and the necessity for collective action at a regional level to influence socio-economic development. Moreover, it made them aware that local decisions on future land use may influence the effects of climate change. Consistent storylines helped stakeholders to visualize a desired future and to see their scope of influence. The transdisciplinary research process allowed local stakeholders to translate the hydrological modelling results into a concrete local CCA strategy.

The presented approach describes a model for a rule-based expert system calculating the temporal variability of the release of wet snow avalanches, using the assumption of avalanche triggering without the loading of new snow. The knowledge base of the model is created by using investigations on the system behaviour of wet snow avalanches in the Italian Ortles Alps, and is represented by a fuzzy logic rule-base. Input parameters of the expert system are numerical and linguistic variables, measurable meteorological and topographical factors and observable characteristics of the snow cover. Output of the inference method is the quantified release disposition for wet snow avalanches. Combining topographical parameters and the spatial interpolation of the calculated release disposition a hazard index map is dynamically generated. Furthermore, the spatial and temporal variability of damage potential on roads exposed to wet snow avalanches can be quantified, expressed by the number of persons at risk. The application of the rule base to the available data in the study area generated plausible results. The study demonstrates the potential for the application of expert systems and fuzzy logic in the field of natural hazard monitoring and risk management.

The uptake of information and communication technologies in the classrooms is a key trend over the past years and decades. Teachers are using Moodle courses, e-Portfolios, Google Docs, perhaps learning games or virtual worlds such as OpenSim for educational purposes. A second trend pushes towards a formatively inspired assessment and feedback, often combined with attempts of educational data mining and learning analytics. In this paper we present a role model for teaching English as a second language using OpenSim and a tool that enables teachers to perform real-time learning analytics and direct formative feedback and interventions in the virtual learning session. Also we present an approach to aggregate and store the learning information into open learner models.

Measurement of clock gene expression has recently provided evidence that the cerebellum, like the master clock in the SCN, contains a circadian oscillator. The cerebellar oscillator is involved in anticipation of mealtime and possibly resides in Purkinje cells. However, the rhythmic gene expression is likely transduced into a circadian cerebellar output signal to exert an effective control of neuronal brain circuits that are responsible for feeding behavior. Using electrophysiological recordings from acute and organotypic cerebellar slices, we tested the hypothesis whether Purkinje cells transmit a circadian modulated signal to their targets in the brain. Extracellular recordings from brain slices revealed the typical discharge pattern previously described in vivo in single cell recordings showing basically a tonic or a trimodal-like firing pattern. However, in acute sagittal cerebellar slices the average spike rate of randomly selected Purkinje cells did not exhibit significant circadian variations, irrespective of their specific firing pattern. Also, frequency and amplitude of spontaneous inhibitory postsynaptic currents and the amplitude of GABA- and glutamate-evoked currents did not vary with circadian time. Long-term recordings using multielectrode arrays (MEA) allowed to monitor neuronal activity at multiple sites in organotypic cerebellar slices for several days to weeks. With this recording technique we observed oscillations of the firing rate of cerebellar neurons, presumably of Purkinje cells, with a period of about 24 hours which were stable for periods up to three days. The daily renewal of culture medium could induce circadian oscillations of the firing rate of Purkinje cells, a feature that is compatible with the behavior of slave oscillators. However, from the present results it appears that the circadian expression of cerebellar clock genes exerts only a weak influence on the electrical output of cerebellar neurons.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) represent a new class of photoreceptors which support a variety of non-image forming physiological functions, such as circadian photoentrainment, pupillary light reflex and masking responses to light. In view of the recently proposed role of retinal inputs for the regulation of diurnal and nocturnal behavior, we performed the first deep analysis of the ipRGC system in a diurnal rodent model, Arvicanthisansorgei, and compared the anatomical and physiological properties of ipRGCs with those of nocturnal mice. Based on somata location, stratification pattern and melanopsin expression, we identified two main ipRGC types in the retina of Arvicanthis: M1, constituting 74% of all ipRGCs and non-M1 (consisting mainly of the M2 type) constituting the following 25%. The displaced ipRGCs were rarely encountered. Phenotypical staining patterns of ganglion cell markers showed a preferential expression of Brn3 and neurofilaments in non-M1 ipRGCs. In general, the anatomical properties and molecular phenotyping of ipRGCs in Arvicanthis resemble ipRGCs of the mouse retina, however the percentage of M1 cells is considerably higher in the diurnal animal. Multi-electrode array recordings (MEA) identified in newborn retinas of Arvicanthis three response types of ipRGCs (type I, II and III) which are distinguished by their light sensitivity, response strength, latency and duration. Type I ipRGCs exhibited a high sensitivity to short light flashes and showed, contrary to mouse type I ipRGCs, robust light responses to 10 ms flashes. The morphological, molecular and physiological analysis reveals very few differences between mouse and Arvicanthis ipRGCs. These data imply that the influence of retinal inputs in defining the temporal niche could be related to a stronger cone input into ipRGCs in the cone-rich Arvicanthis retina, and to the higher sensitivity of type I ipRGCs and elevated proportion of M1 cells.