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Toward Dynamic Phase-Field Fracture at Finite Strains
No full textWe investigate the evolution of dynamic phase-field fracture in the finite-strain setting, extending our previous work in the small-strain viscoelastodynamic regime. The elastodynamic equations are coupled with a dissipative damage evolution for the phase-field variable . The material response is described with a polyconvex stored energy density = ( , , , ) , where denotes the gradient of the deformation, its cofactor, and its determinant. This ensures compatibility with the principles of nonlinear elasticity. A fully discrete time-staggered approximation scheme is proposed, along with associated stability of discrete solutions. We present compactness results and analyze the convergence of the discrete approximations. While convergence of the phase-field variable and the compatibility of the kinematic variables can be demonstrated, the identification of the limit stress in the momentum balance remains open. To address this, two strategies are outlined: an extension of the classical (weak) framework using generalized Young or defect measures, and an alternative formulation via energetic-variational solutions that avoids the explicit measure construction. Partial results on existence and the structure of the limit system are discussed
Weather fluctuations and the (German) industrial sector
No full textWe contribute to the recent literature on the economic effects of those weather conditions that deviate from their regular seasonal pattern. To this end we use local temperature and snow measurements across Germany to analyze their impact on German monthly industrial and construction-sector production. We find noticeable effects of the various (linear and nonlinear, contemporaneous and dynamic) weather regressors, which in the –seasonally adjusted– construction sector growth data imply an extra explanatory power of more than 35% of the variation, compared to benchmark predictive regressions with usual leading indicators. As expected, the impact is quite a bit less in industrial production, in the single-digit range. From our estimates we obtain (seasonally as well as) weather adjusted production series. We also assess the forecasting contribution in pseudo real time settings where publication lags are taken into account, and we apply model averaging techniques to analyze the relevance of abnormal weather for recession forecasting in probit models
Treatment pathways of lipid-lowering therapies in Germany 2016–2022
No full textBackground
Despite the availability of effective LDL cholesterol (LDL-C)-lowering drugs, only a minority of patients achieves the guideline-recommended treatment targets. This analysis describes treatment pathways of lipid-lowering therapy (LLT) in Germany.
Methods
Health claims data were used to identify patients at high or very-high cardiovascular risk who received a LLT prescription 2016–2022. Treatment pathways and the time to switch or discontinue LLT were analysed for statins, ezetimibe, bempedoic acid (BA), and PCSK9 inhibitors (PCSK9i).
Results
Out of 3,487,827 insured persons, 247,529 met the inclusion criteria. The most frequent first-line LLT were statins in 96.3%. Ezetimibe, BA, and PCSK9i were first-line LLT in only 0.9%, 0.061%, and 0.046%, respectively. Only few patients experienced a change in their treatment regimen following LLT initiation. Prescriptions of BA and PCSK9i were mainly second-, third-, or fourth-line add-on treatment. Termination of treatment with BA and PCSK9i was less frequent compared to statins and ezetimibe. The median time to treatment discontinuation was 1.45, 1.04, 0.60, and 2.45 years for statins, ezetimibe, BA, and PCSK9i, respectively, and the median time to switch therapy was 4.81 and 4.87 years for ezetimibe and PCSK9i, respectively (median not reached for statins and BA).
Conclusions
Changes in LLT were only observed in a minority of patients. BA and PCSK9i were switched more frequently than statins and ezetimibe. BA was discontinued earlier, and PCSK9i later than the other agents. Continued efforts to maintain long-term adherence and overcome therapeutic inertia are needed to realise the potential of available LLT with proven cardiovascular benefit
Phylogenetic and structural analyses reveal Cdc2-like kinases (CLKs) as ancient regulators of thermosensitive splicing
No full textThe family of Cdc2-like kinases (CLKs) plays a critical role in regulating both constitutive and alternative pre-mRNA splicing. Of particular interest, CLKs exhibit unique thermosensitive properties characterized by increased activity at lower physiological temperatures. In this study, we integrate phylogenetic, protein-interaction, and structural analyses to investigate the evolutionary history and functional adaptation of CLKs across protista, fungi, plants, and metazoans. Our phylogenetic analysis, comprising 149 CLK homologs from 86 species, traces this gene back to the last eukaryotic common ancestor. The results reveal lineage-specific patterns of gene duplication and loss, including complete loss of CLKs in seven protist lineages and in microsporidian fungi. Interolog mapping identified 92 conserved CLK-interacting proteins across diverse species. In metazoans, these conserved interactors are primarily involved in complex splicing regulation, whereas in yeast they are associated with simplified RNA-processing mechanisms. Comparative structural modeling shows strong conservation of the kinase domain throughout eukaryotes, although notable divergence occurs in some Fungal and Protista lineages. Intrinsic disorder in the CLK N terminus emerges as a conserved structural property; however, sequence variability in this region modulates kinase activity and substrate specificity. Structural conservation in the activation segment, the core driver of CLK thermosensitivity, is observed across all eukaryotic kingdoms, though deviations were identified in various protist and plant lineages. Deleterious mutations often occur in this region following a duplication or preceding complete gene loss. Finally, species-specific temperature activity profiles underscore the adaptive evolution of CLKs, enabling organisms to thrive in diverse environmental conditions, including extreme temperatures
Extreme summer storm elicits shifts in biogeochemistry, primary productivity, and plankton community structure in a large-scale lake enclosure experiment
No full textClimate change increases the magnitude and frequency of extreme weather events. This includes severe summer storms altering lake physical structure, biodiversity and ecosystem processes. However, insights into lake responses to extreme storms and the underlying mechanisms primarily rest on unreplicated and observational case studies, without separating effects of physical forcing from secondary drivers such as external nutrient and dissolved organic matter inputs. In a large-scale replicated experiment conducted in a unique enclosure facility mimicking realistic environmental conditions, we tested how storm-induced mixing entails changes in lake ecosystems. Consequences include altered phytoplankton composition, nutrient, oxygen and carbon dynamics, with potential negative feedbacks on climate through organic matter sequestration. These experimental results are reflected in a minimal dynamical model and are also supported by observations made during a natural severe storm. An important practical implication is that efforts to abate lake eutrophication needs to accommodate the projected increases in extreme weather situations
Origins, endings and temporal pluralities: Bayesian perspectives on the Kura-Araxes phenomenon
No full textThe Kura-Araxes culture spread over a large area of South-west Asia, participating in the transformational dynamics of Early Bronze Age societies in the region. Yet, the absence of a robust chronological framework for this cultural horizon hinders its integration into wider regional and interregional models. Drawing on a substantial new radiocarbon dataset, collating novel Bayesian chronological models for eight sites and existing data from the wider region, this article identifies settlement patterns that coincide with broader reconfigurations of the Kura-Araxes cultural landscape, which in turn track socioeconomic, and possibly political, shifts observed in eastern Anatolia and the greater Near East
Telecological Collapse: The Inevitability of Climate Breakdown in the Transmedial Podcast Drama Forest 404
No full textThis paper presents a close-hearing analysis of Forest 404, a transmedial audio drama that was released to BBC Sounds in 2019. Despite the drama's eco-dystopian critique of teleological ‘progress’ narratives (that enable and perpetuate the destruction of the natural world), I argue that the series ultimately propagates a sense of inevitability surrounding climate breakdown. Terming this inevitability ‘telecological collapse’, I draw upon critiques of linear time that associate Western teleology with colonial practices of expansion, accumulation and environmental devastation. Foregrounding the series' transmedial reach as a project that encompasses, not simply dramatic episodes but also an academic experiment, soundscapes of the natural world, and post-show podtalks, I consider how the series presents a transmedial reckoning with climate change within a specifically national British media context. When analysing the biophonic preoccupations of Forest 404, this involves reference to Estok's opposing concepts of ‘ecophobia’ and ‘biophilia’ as an ecocritical approach attentive to a history of colonial domination and the fetishisation of the natural world. Concluding with attention to the drama's ending, in which the lone-surviving protagonist retreats into an individuated realm of digital simulations, the paper hence raises questions about the role of climate narratives in reinforcing the notion that the only path of mitigation with regards to environmental breakdown involves surrendering the physical and material beauty of the natural world to the dogma of techno-solutionism
Further Insights Into the Metabolism of LGD-4033 in Human Urine. Part 2. A New Minor Metabolite With Antagonistic Activity on the Androgen Receptor Can Indicate Recent Substance Intake
No full textUsing a targeted metabolic investigation approach, a new, previously undescribed metabolite, which is a pyrrole derivative of LGD-4033, has been detected and coded as M8. This metabolite can be detected in postadministration human urine samples up to 6 days after administration. It has also been detected in post-administration samples, mimicking supplement contamination, after repeated 10 μg doses detectable for ≥ 120 h after administration. Given M8's structural similarity to LGD-4033, its androgen receptor (AR) agonist/antagonist properties were studied using in silico molecular docking and functional in vitro AR transactivation assays in the PC3(AR)2 cell model, alongside other selected LGD-4033 metabolites. The results indicate that M8 can act as a potent AR antagonist, whereas M2c was reconfirmed as a potent AR agonist. Therefore, we propose the inclusion of M2c in ITP doping control methods, as it could be used as an LGD-4033 alternative and may be introduced into the black market. Additionally, the detection of M8, which is an early-stage excreted metabolite, is valuable for estimating sample collection time relative to LGD-4033 intake. When combined with the evaluation of other long-term metabolites like M5b, M5a, M2c, and M2d, M8 detection can aid in distinguishing adverse analytical findings, associated abuse through regular dosing, from unintentional doping caused by certain contamination scenarios or abuse through microdosing
Diverse crop rotations offset yield-scaled nitrogen losses via denitrification
No full textDenitrification, a major source of gaseous nitrogen emissions from agricultural soils, is influenced by management. Practices promoting belowground diversity are suggested to support sustainable agriculture, but how they modulate nitrogen losses via denitrification remains inconclusive. Here we sampled 106 cereal fields spanning a 3000 km North-South gradient across Europe and compiled 56 associated climatic, soil, microbial and management variables. We show that increased denitrification potential was associated with higher proportion of time with crop cover over the last ten years and was best predicted by microbial biomass and microbial functional guilds involved in nitrogen cycling, in particular denitrification. We also demonstrate that several diversification practices affect the variation in denitrification potential predictors, suggesting a trade-off between agricultural diversification and nitrogen losses via denitrification. However, increased crop diversity in rotations improved yield-scaled denitrification, highlighting the potential of this practice to minimize nitrogen losses while contributing to sustainable food production
Comparative Buffer and Spacer Layer Engineering in Co/Pt-Based Perpendicular Synthetic Antiferromagnets
No full textPerpendicular magnetic tunnel junctions (p-MTJs) rely on synthetic antiferromagnets (SAFs) as reference layers to achieve strong perpendicular magnetic anisotropy (PMA) together with stable interlayer exchange coupling. In this study, we present a comparative materials study of buffer and spacer layer engineering in Co/Pt-based perpendicular synthetic antiferromagnets (p-SAFs). The influence of buffer layer selection, number of multilayer repeats, and annealing at 330 °C for 30 min on PMA and interlayer exchange coupling is systematically examined. Co/Pt multilayers with four and six repeats were grown on Ta/Ru and Ta/CuN buffer layers separately, followed by the fabrication of SAF structures incorporating Ru spacers with thickness between 0.60 and 0.80 nm. Magnetic measurements show that Ta/Ru-buffered structures exhibit squarer hysteresis loops, higher remanence, and greater tolerance to annealing at 330 °C for 30 min compared to Ta/CuN-buffered counterparts. The SAF structures display clear two-step magnetization reversal and robust antiferromagnetic coupling across the investigated Ru thickness range, with large exchange fields and bias fields in the deposited state. Although annealing reduces the absolute coupling strength, a Ru spacer thickness of 0.60 nm retains the strongest antiferromagnetic response within the studied thermal budget. These results underscore the importance of comparative buffer and spacer layer engineering and provide materials insights into the design of Co/Pt-based p-SAF reference stacks that may inform future p-MTJ structures