In 1982, Bartnik and Simon proved that area maximizing hypersurfaces are smooth, strictly spacelike and maximal (mean curvature zero) away from a singular set which consists of light rays connecting boundary points. Around the same time, Leon Simon conjectured that area maximizing hypersurfaces ought to be of class C^{1,1} across their singular set, and pointed out that, if correct, this regularity statement could not be improved to C^2 in view of a certain example. In this paper, we prove Leon Simon’s conjecture.

roadband optical pulses with attosecond to femtosecond durations provide unique opportunities for studies of time-resolved electron dynamics. However, focusing these pulses—typically ranging from the vacuum ultraviolet to the soft-X-ray region—remains challenging. Conventional refractive lenses are not suitable owing to large dispersion and strong absorption, whereas reflective optics do not suffer from these issues but have high losses. Here we demonstrate a tunable hydrogen plasma lens to focus broadband extreme-ultraviolet attosecond pulses with energies of around 20 eV and 80 eV. Simulation results suggest that the stretching of attosecond pulses is negligible, and temporal compression is possible when atto-chirp is included. A key advantage of the plasma lens is its compatibility with nonlinear frequency conversion processes like high-harmonic generation. The different focusing properties of the fundamental and harmonic frequencies allow for an efficient separation of these components. Consequently, the transmission of high-harmonic generation beamlines can be increased to more than 80% and this approach can be suitable for applications requiring high photon flux.

Opioids remain a cornerstone of pain management, but currently used therapeutics are associated with serious side effects. While κ-opioid receptor (KOR) agonists offer an alternative to classical μ-opioid receptor (MOR) agonists, their clinical potential is limited by severe adverse effects. G protein-biased KOR agonists are a promising strategy for developing safer analgesics. In this study, we used virtual screening to develop novel dual-charged naltrexamine amide derivatives as tool compounds for investigating biased agonism at the KOR. All of the predicted ligands demonstrate low-nanomolar activity and G protein bias at both the KOR and MOR. Molecular dynamics simulations revealed a key allosteric communication involving TM4, TM5, and ICL2. These compounds achieve their effects through interactions with residues E209ECL2, D2235.35, E2976.58, and K2275.39. These findings provide insight into the structural mechanisms of KOR signaling bias and inform the rational design of improved KOR therapeutics.

The current loss of freshwater biodiversity calls for immediate action, including the mobilisation of existing data and tools to support long-term conservation. Yet, establishing a global baseline for the spatial distribution of freshwater habitats and the biodiversity they host remains difficult. Such task would require standardized, high-resolution environmental information to characterise freshwater habitats anywhere in the world. To address this challenge, we present the Environment90m dataset, which aggregates a large number of environmental layers into each of the 726 million sub-catchments of the Hydrography90m dataset, corresponding to single stream segments. Specifically, Environment90m includes 45 variables related to topography and hydrography, 19 climate variables for the observation period of 1981–2010, as well as projections for 2041–2070 and 2071–2100 under the Shared Socioeconomic Pathways (SSPs) 1.26, 3.70 and 5.85, and three global circulation models (UKESM1-0-LL, MPI-ESM1-2-HR and IPSL-CM6A-LR). Moreover, Environment90m includes 22 land cover categories for the annual time-series data from 1992–2020. In addition, we provide 15 soil variables and information on aridity and modelled streamflow. Summary statistics (i.e., mean, min, max, range, sd) are provided for all continuous variables, while for categorical data, the proportion of each category is calculated within each of the sub-catchments. The data is available at https://hydrography.org/environment90m (last access: 4 February 2026). To facilitate data download and processing, we provide dedicated functions within the hydrographr R-package, and extend these also to new functions for processing upstream data of lakes. For all underlying calculations, we used the open-source tools GDAL/OGR, GRASS-GIS and AWK, so that custom data can be easily generated using the hydrographr R-package. Environment90m, along with the tools, provides an array of opportunities for research and application in spatial freshwater biodiversity science, specifically biogeographic analyses and conservation exercises in freshwater ecosystems. The metadata of the Environment90m dataset is stored at 10.18728/igb-fred-995.0 .

Auf Grundlage eines umfassenden empirischen und theoretischen Wissens haben sich didaktische Grundpositionen etabliert, die normativ modellieren, wie qualitätsvoller arithmetischer Anfangsunterricht gestaltet sein sollte. Zugleich verweisen Studien darauf, dass der arithmetische Anfangsunterricht den aus fachlicher Perspektive formulierten Qualitätsansprüchen nicht gerecht wird. Im Rahmen dieses Beitrags wird der Eindruck einer Entfachlichung des arithmetischen Anfangsunterrichts empirisch fundiert: Einerseits werden aus mathematikdidaktischen Lehrbüchern die Qualitätsnormen identifiziert, die stabile Bezugspunkte für eine Didaktik des arithmetischen Anfangsunterrichts bilden. Andererseits werden Praktiken rekonstruiert, die sich im Rahmen eines ethnographischen Forschungsprojekts als typisch für den arithmetischen Anfangsunterricht erwiesen haben. Die Gegenüberstellung von Qualitätsnormen und typischen Praktiken verweist darauf, dass letztere die von Seiten der Mathematikdidaktik formulierten Qualitätsansprüche verletzen. Aus praxistheoretischer Perspektive ist solch eine Verletzung fachlich orientierter Qualitätsnormen nicht überraschend. Die festgestellten Normbrüche werden im Rahmen dieses Beitrags deshalb einer funktionalen Analyse unterzogen. Es zeigt sich, dass sich die typischen Praktiken trotz ihrer fachlichen Normbrüchigkeit zugleich als funktional erweisen: Sie sind anschlussfähig an eine Eigenlogik des „Schule-Haltens“ und tragen so zur Lösung von Problemen bei, die sich gerade in der Anfangsphase eines schulisch organisierten Mathematikunterrichts in besonderem Maße stellen.

Covalent inhibitors and chemical probes targeting ligandable cysteine residues have emerged as powerful tools for drug discovery and proteomics. In this study, we introduce vinyl phosphonamidates (VPAs) as a novel class of latent cysteine electrophiles and assess their reactivity, selectivity, and potential for developing covalent inhibitors. Compared to well-established chloroacetamide and acrylamide electrophiles, VPAs exhibit a significantly lower intrinsic reactivity toward the model thiol glutathione. Moreover, VPA-derived covalent fragments displayed only very limited nonspecific reactivity in human cell lysate. Encouraged by these results, we developed VPA-functionalized derivatives of the FDA-approved covalent inhibitors Afatinib and Ibrutinib and evaluated their ability to engage the target protein by gel-based and mass spectrometry-based activity-based protein profiling (ABPP). Compared to commonly employed Michael acceptor-based electrophilic groups, VPA-functionalized drug ligands displayed significantly less off-targets while maintaining inhibitor efficiency. Furthermore, we leveraged the modular nature and accessibility of VPAs to develop a bifunctional proteolysis targeting chimera (PROTAC) for targeted protein degradation. The demonstrated selectivity and modularity, as exemplified by the incorporation of various ligands on the phosphorus O -substituent, of the vinyl phosphonamidate group as a cysteine-directed electrophile highlight its ability to expand the chemical space in the development of covalent inhibitors with a favorable proteome-wide reactivity profile.

Polyuronic acids are important biopolymers in marine organisms, where they contribute to extracellular matrix modulation, cell signaling, and carbon cycling. However, the intrinsic structural heterogeneity of polyuronic acids has hindered efforts to establish clear structure–function relationships. Here, we report an automated glycan assembly (AGA) approach that enables the precise synthesis of β-(1–4)-linked d -glucuronic acid (GlcA) oligomers with defined chain lengths and glycosidic linkage stereochemistry. Molecular dynamics simulations revealed a characteristic 2-fold helical conformation, with rigidity in short oligomers and enhanced flexibility emerging in longer sequences. The calcium binding behavior of these oligomers was explored by NMR titrations, revealing diffuse electrostatic binding rather than localized chelation. Polyglucuronic acid (PGA) oligomers are a well-defined molecular model for dissecting ion-mediated interactions and provide a framework for designing uronic acid-based glycomaterials with tunable properties.

Amphiphilic nanogels (ANGs) are promising colloidal carriers to improve bioavailability of poorly water-soluble drugs. In contrast to conventional hydrophilic nanogels, ANGs contain additional hydrophobic domains in their network to load hydrophobic cargos. However, optimizing drug loading remains labour-intensive due to the lack of quantitative tools that accurately capture the complex ANG–drug interactions. To address this limitation and assess drug compatibility, we developed a quantitative framework based on Flory–Huggins interaction parameters ( χ ). Key to our approach is the empirical adjustment of the correction factor α to account for unequal contributions of dispersion forces, polar interactions, and hydrogen bonds. Using a model ANG and a library of hydrophobic drugs and dyes, we established selection rules for α based on the dominant interaction type: α = 1 for dispersion-dominated, α = 0.7 for polar, and α = 0.3 for hydrogen bond-dominated systems. This enabled systematic grouping of cargos and revealed strong monotonic negative correlations between adjusted χ values and experimental loading capacities. The resulting universal calibration curve links χ to drug loading content across diverse ANG–drug systems. Consequently, our framework suggests predictive potential of solubility parameter-based models, reduces experimental burden, and supports the rational design of ANG carriers tailored to specific hydrophobic drugs.

Do people change climate-related opinions when they learn that thousands protested? Two survey field experiments tested how turnout at major climate demonstrations shaped politically interested individuals’ views in a German national election. Turnout significantly increased perceived movement efficacy, especially among more involved participants, and potentially increased internal political efficacy. Pro-environmental attitudes and vote intentions remained unchanged. Protest days appear to signal collective capacity rather than drive immediate attitude change.

Hyperketonemia (HYK), defined by blood beta-hydroxybutyrate (BHB) ≥ 1.2 mmol/L, is described as a significant risk factor for cows developing postpartum (pp) diseases and impaired reproductive performance. The goal of the present study was to observe metabolic challenges in transition cows and to identify systemic markers reflecting HYK associated with lessened reproductivity. Fifty-four Simmental cows were monitored, revealing approximately 30% prevalence of HYK at the early pp period on 7, 14, or 28 days in milk (DIM). We assessed the dry matter intake, rumination time (RT), serum liver activity index, non-esterified fatty acids (NEFAs), acute phase proteins, and uterine and oviductal health. Elevated NEFA and reduced RT 14 days antepartum were a good predictor for HYK at 7 DIM. Hyperketonemia at 14 DIM resulted in higher milk yield compared with controls. We could neither detect differences in uterine health nor in reproductive key performance parameters between hyperketonemic and control cows, whereby the proportion of polymorphonuclear neutrophils in oviductal epithelia was significantly lower in hyperketonemic cows 14 DIM. We conclude that elevated concentrations of BHB in HYK 7, 14, or 28 DIM indicated energy supply to support physiological metabolic adaptations and lactation and that, in the absence of excessive inflammation during the transition period, HYK was not a risk factor for impaired fertility.

Clinical rotations are an integral part of the veterinary curriculum. Their effect on knowledge, skills and self-perception, however, has been poorly investigated. The aim of this study was to evaluate the effect of a structured small animal clinical rotation on veterinary students in these three areas. Participating students were asked to complete an online questionnaire with questions assessing knowledge, skills and self-perception before and after their clinical rotation. A total of 61 students completed the questionnaire before and 43 after the clinical rotation, leading to 41 pre-post matches for self-assessment of skills and self-perception and 39 pairs for knowledge-based questions. The percentage of correctly answered knowledge-based questions increased statistically significantly but only by one correct answer on average. Participants rated their skills in performing specific tasks significantly higher after the clinical rotation compared to before. All participants assessed themselves as competent at history taking, performing a general examination and endotracheal intubation after the clinical rotation. However, 30–40% of participants disagreed at least partly with the sentence that they can perform neurological and ophthalmological examinations as well as interpret blood results on their own after the clinical rotation. Participants rated themselves significantly higher regarding their self-perception in the role of small animal practitioner after the clinical rotation than at the start of the rotation. The study indicated that the clinical rotation improved students’ self-assessment of their skills and attitude but did not lead to a significant improvement in knowledge.

It is known that rainfall leads to a reduction in driving speed. However, the results of various studies are inconsistent regarding the amount of speed reduction. In this study, we combine high-resolution radar-based rainfall estimates for three days with heavy rainfall with driving speeds derived from floating car data on 1.5 million road sections in Germany. Using linear regression models, we investigate the functional relationship between rainfall and driving speeds depending on road section characteristics like speed limit and number of lanes. We find that the speed reduction due to rainfall is higher at road section with higher speed limits and on multi-lane roads. On highway road section with speed limits of 130 km/h, for example, heavy rainfall of more than 8 L/m2 in five minutes leads to an average speed reduction of more than 30%, although estimates at very high rainfall intensities are subject to increased uncertainty due to data sparsity. Cross-validation shows that including rainfall as a predictor for driving speed reduces mean squared errors by up 14% in general and up to 50% in heavy rainfall conditions. Furthermore, rainfall as a continuous variable should be preferred over categorical variables for a parsimonious model. Our results demonstrate that parsimonious, interpretable models combining radar rainfall data with floating car data can capture systematic rainfall-related speed reductions across a wide range of road types. However, the analysis should be interpreted strictly as a descriptive, event-specific study. It does not support generalizable inference across time, seasons, or broader traffic conditions. To make this approach suitable for operational applications such as real-time speed prediction, route planning, and traffic management, larger multi-event datasets and the consideration of effects like weekday structure and diurnal demand patterns are required to better constrain effects under heavy rainfall conditions.

Continuous digital monitoring of sheep behaviour shows potential for early stress detection. In Part 1 of this study, a novel accelerometer-based behaviour-recognition system using a nRF52832 microcontroller with Bluetooth wireless data transfer was developed and validated. A dedicated algorithm was developed to focus on the automatic detection of rumination, which also enables the classification of resting/idling and eating. The system achieved accuracies of 0.87 (rumination), 0.90 (resting/idling), and 0.86 (eating). Specificities were 0.87, 0.95, and 0.94; sensitivities 0.89, 0.80, and 0.60; and precisions 0.79, 0.88, and 0.73, respectively. In Part 2, four sheep were continuously monitored for 24 h to establish baseline behavioural durations. Animals were then relocated in pairs to an unfamiliar enclosure for a further 24 h observation period. Relocation resulted in a significant reduction in rumination time (−45.6%, p < 0.05) and a significant increase in resting/idling (+47.9%, p < 0.05), while time spent eating decreased but did not reach statistical significance (−36.2%). These findings indicate that detecting deviations from baseline rumination and resting/idling durations may serve as suitable ethological parameters for automated, sensor-based stress alerts. With further technical refinement and validation, the developed system shows strong potential as a reliable, non-invasive tool for monitoring key sheep stress indicators.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) and Acinetobacter baumannii (CRAB) pose significant therapeutic challenges due to their high resistance and global spread. Combination therapy with colistin (COL) and meropenem (MEM) was used to enhance antimicrobial activity. This study evaluated the COL-MEM combination against CRKP and CRAB isolates with a high resistance profile. A total of 58 carbapenem-resistant clinical isolates (31 CRKP and 27 CRAB), including extensively resistant and pandrug-resistant strains, were collected over a period of 12 months. Synergy between COL and MEM was assessed by microdilution checkerboard (MCB) and time-kill (TKA) assays. Carbapenemase genes were detected using molecular methods. The results showed that the COL-MEM combination yielded synergy (35.5% and 40.7%, respectively) and additive effects (35.5% and 37.0%, respectively), while no antagonism was observed. TKA confirmed bactericidal activity, especially at doubled MCB-detected concentrations, indicating dose-dependent activity. The significant reduction in the minimum inhibitory concentration in the combination indicated its potential for dose optimization, minimizing COL-associated toxicities. Genotypic profiling showed that the expression of blaNDM and blaOxa-48 can reduce synergy. These findings, obtained with isolates of high resistance, support the efficacy of this combination therapy and could reduce the dose-related side effects of COL. However, they also highlight genotype-specific variations and COL resistance mechanisms as limiting variables.

Dietary fiber (DF) is a fundamental component of animal nutrition and has been widely studied for its nutritional and physiological functions in animals. While existing studies mainly focus on the independent effects of DF on gut microbiota or bile acids (BAs), the mechanisms underlying their interactions remain poorly understood. DF interacts closely with gut microbiota, promoting the production of beneficial metabolites such as short-chain fatty acids, which subsequently influence BA metabolism through microbial deconjugation and dehydroxylation processes, generating free and secondary BA essential for host health. Together, the gut microbiota and BA play key roles in mediating the effects of DF on intestinal and systemic physiology via the gut–liver axis. Although DF contributes to energy supply, nutrient digestion, and regulation of gut microbiota and BA metabolism, its physiological effects vary depending on fiber source, type, chemical composition, inclusion level, and animal species. Ruminant and non-ruminant animals differ in their capacity to utilize DF, with extensive fermentation occurring in the rumen of ruminants, whereas fermentation in non-ruminants mainly occurs in the hindgut and is more limited. Consequently, inappropriate DF supplementation may impair gastrointestinal function and overall physiological status. This review summarizes the diverse effects of different DF types in animals and critically examines the complex and bidirectional interactions among DF, gut microbiota, and BA metabolism, highlighting knowledge gaps that require further investigation to optimize DF application in animal nutrition.

Two-dimensional arrays of ballistic Josephson junctions are important as model systems for synthetic quantum materials. Here, we investigate arrays of multiterminal junctions which exhibit a phase difference 𝜑0 at zero current. When applying an in-plane magnetic field, we observe nonreciprocal vortex depinning currents. We explain this effect in terms of a ratchetlike pinning potential, which is induced by spontaneous supercurrent loops. Supercurrent loops arise in multiterminal 𝜑0 junction arrays as a consequence of next-nearest-neighbor Josephson coupling. Tuning the density of vortices to commensurate values of the frustration parameter results in an enhancement of the ratchet effect. In addition, we find a surprising sign reversal of the ratchet effect near frustration 1/3. Our work calls for the search for novel magnetic structures in artificial crystals in the absence of time-reversal symmetry.

Das Studium der Veterinärmedizin in Deutschland umfasst extramurale Praktika, in denen Praktikumstierärzt:innen wesentlich zur Ausbildung der Studierenden beitragen. Ziel dieser Studie war es, die Erfahrungen und Bedürfnisse von Praktikumstierärzt:innen sowohl als Lehrende als auch als Lernende zu erfassen, um Grundlagen für ein passgenaues Fortbildungsangebot zur didaktischen Qualifizierung zu schaffen.

Hierzu wurden zwischen März und Juli 2024 leitfadengestützte Expert:inneninterviews mit zehn Praktikumstierärzt:innen aus verschiedenen Tätigkeitsfeldern durchgeführt. Die Interviews wurden transkribiert, anonymisiert und mithilfe einer qualitativen Inhaltsanalyse nach Mayring ausgewertet.

Die Befragten beschrieben ihre Rolle insbesondere in der Einführung der Studierenden in den Berufsalltag, der Vermittlung theoretischer, praktischer und kommunikativer Kompetenzen sowie in der Förderung von Motivation, Selbstfürsorge und eines professionellen Selbstverständnisses. Als Herausforderungen wurden heterogene Vorkenntnisse der Studierenden und Defizite der universitären Ausbildung benannt, die in den Praktika ausgeglichen werden müssten. Hinsichtlich ihrer eigenen Lernbedürfnisse betonten die Praktikumstierärzt:innen, die Bedeutung eines Praxis- und Anwendungsbezugs, den Einfluss der Lehrenden, Interaktivität sowie den Wunsch nach zeit- und kosteneffizienten und flexiblen Fortbildungsformaten.

Diese Ergebnisse liefern Hinweise für potenzielle Inhalte eines didaktischen Fortbildungsangebot für Praktikumstierärzt:innen. Methodisch sollte ein solches Angebot praxisorientiert, fallbasiert und interaktiv gestaltet sein, Möglichkeiten für den kollegialen Austausch bieten sowie zeitlich und organisatorisch mit der Berufstätigkeit vereinbar sein.

After periprosthetic joint infection (PJI)-dependent revision surgery, a significantly elevated number of patients suffer from prosthesis failure due to aseptic loosening and require additional revision surgery despite clearance of the initial infection. The mechanisms underlying this pathology are not well understood, as it has been assumed that the bone stock recovers after revision surgery. Despite clinical evidence suggesting decreased osteogenic potential in PJI, understanding of the underlying biology remains limited. In this study, we investigated the impact of PJI on bone homeostasis in a two-stage exchange approach at explantation and reimplantation. Sixty-four human tibial and femoral specimens (20 control, 20 PJI septic explantation, and 24 PJI prosthesis reimplantation samples) were analyzed for their bone microstructure, cellular composition, and expression of relevant genetic markers. Samples were analyzed using X-ray microtomography, Alcian blue and tartrate-resistant acid phosphatase staining, and RT-qPCR. In patients with PJI, bone volume (BV/TV; 0.173 +/- 0.026; p < 0.001), trabecular thickness (164.262 +/- 18.841 mu m; p < 0.001), and bone mineral density (0.824 +/- 0.017 g/cm(2); p = 0.049) were reduced; trabecular separation (1833.939 +/- 178.501 mu m; p = 0.005) was increased. While prevalence of osteoclasts was elevated (N.Oc/BS: 0.663 +/- 0.102, p < 0.001), osteoblast cell numbers were lower at explantation (N.Ob/BS: 0.149 +/- 0.021; p = 0.047). Mean expression of bone homeostasis markers osteocalcin, osteopontin, Runx2, TSG-6, and FGF-2 was significantly reduced at prosthesis explantation. Despite partial recovery, all analyzed parameters were still significantly impacted at reimplantation. In contrast, mean expression of osteoclastogenesis-stimulating cytokine IL-17a was significantly increased at both explantation and reimplantation. In this study, we found a strong and lasting impact of PJI on the bone homeostasis on a molecular, cellular, and microstructural level. These changes may be responsible for the increased risk of prosthesis failure due to aseptic loosening. Our data suggest there is significant potential in modulating bone homeostasis to improve prosthesis fixation and long-term clinical outcome in affected patients. (c) 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).