144444 research outputs found
Sort by
Light-induced analgesia provides a drug-free optical method for pain relief via activation of TRAAK k+ channels
No full textAbstract Pain management in animal experimentation is crucial for both ethical and scientific reasons, as unmanaged pain can distort physiological responses compromising data reliability. Current strategies are often invasive and pharmacology-based, introducing variability and confounding effects. Here, we present Light-Induced Analgesia, a drug-free, non-invasive method for pain relief in animals. We show that 365 nm illumination activates the pain-inhibitory TRAAK two-pore domain potassium (K2P) channel. This activation is driven by the oxidation of a native methionine at TRAAK’s regulatory fenestration site, triggering a conformational switch from its inactive (down) to active (up) state. We further demonstrate that this mechanism can be transferred to other related K2Ps via a single-point mutation, rendering them light-sensitive. In rodents, gentle skin exposure to 365 nm is sufficient to activate endogenous TRAAK, silence nociceptors, and produce potent, long-lasting analgesia that outperforms standard treatments. Light-Induced Analgesia thus offers an effective, drug-free alternative that can enhance animal welfare and experimental reliability in preclinical research
Climatic niche conservatism in non-native plants depends on introduction history and biogeographic context
No full textNiche conservatism is a fundamental assumption in predictive models for managing non-native species, but its generality remains debated due to mixed empirical evidence. We argue that this reflects underexplored context dependencies, as few studies have compared the niche dynamics of species introduced to multiple regions. Here, we quantify climatic niche changes in 1566 introductions of 316 non-native plant species across eight regions, including continents and archipelagos. While niche expansion into previously unoccupied conditions was low, niche conservatism and unfilling varied strongly across regions. Species with small native range sizes exhibited greater niche expansion. Longer residence times reduced niche unfilling, suggesting that a lack of niche conservatism observed in many regions might be transient and potentially linked to dispersal limitations. Our results highlight the necessity to consider region-specific contexts when assessing the potential for niche changes and provide a critical foundation for improving predictive models informing the management of non-native species
Construction of remote dual stereocenters by electrochemical cobalt-catalyzed enantioselective desymmetrization
No full textAbstract The enantio- and diastereoselective construction of two stereogenic centers represents a highly attractive objective in synthetic chemistry. Extensive asymmetric catalytic methods have been developed for the formation of vicinal stereocenters. In contrast, the simultaneous construction of two constitutionally distinct stereogenic centers at remote positions in a single asymmetric catalytic step remains very scarce, owing to the lack of reliable models for distant stereochemical induction for both chiral entities. Herein, we report on an electrochemical cobalt-catalyzed asymmetric hydroacylation of enynes by a desymmetrization strategy that enables the enantio- and diastereo-selective construction of remote dual stereocenters. This unified catalytic platform exhibits broad substrate generality and affords four distinct classes of chiral products, each incorporating two chiral elements: 1,6-central/C–C axial chirality, 1,6-central/C–O axial chirality, 1,5-central/[2.2]paracyclophane planar chirality, and 1,5-central/ferrocene planar chirality
Thermal conductivity of commodity polymers under high pressures
No full textHeat flow in polymers under high-pressure conditions is essential for a range of applications, from aerospace and deep-sea engineering to common lubricants. However, the complex relationship between pressure, P, the thermal transport coefficient, κ, and polymer architecture poses substantial challenges to both experimental and theoretical investigations. In this work, we study the pressure-dependent thermal transport properties of a widely used commodity polymer—poly(methyl methacrylate)—using a combination of all-atom molecular dynamics simulations and semi-analytical approaches. We report both classical and quantum-corrected estimates of κ, both of which show an increase with increasing pressure P. The quantum-corrected approach, which is directly comparable to experiment, reveals that as the pressure increases from 1 atm to 10 GPa, κ rises by nearly a factor of four, from 0.21 to 0.80 W m−1 K−1. By comparison, experimental measurements report an increase from 0.20 to 0.55 W m−1 K−1 over the same pressure range. To better understand the mechanisms behind this increase, we disentangle the contributions from bonded and nonbonded monomer interactions. Our analysis shows that nonbonded energy-transfer rates increase by a factor of six over the pressure range, while bonded interactions show a more modest increase—about a factor of three. This observation further consolidates the fact that nonbonded interactions play the dominant role in dictating the microscopic heat flow in polymers. These individual energy-transfer rates are also incorporated into a simplified heat diffusion model to predict κ. The results obtained from different approaches show internal consistency and align reasonably with available experimental data. In addition, some data for polylactic acid are presented.Bundesministerium für Forschung, Technologie und Raumfahrt 10.13039/50110000234
RHOA controls oncogenic B cell receptor signaling in aggressive lymphoma
No full textDiffuse large B cell lymphoma (DLBCL) is characterized by a variety of specific genetic alterations that impact signaling pathway dependencies and therapeutic outcomes. Among the recurrently mutated genes, we identified RHOA , a member of the small GTPase family, as a selective dependency in DLBCL. Here, we show that RHOA function is essential for the survival of ABC DLBCL cells because it sustains oncogenic B cell receptor (BCR) signaling through maintaining a signaling-permissive conformation of the cortical actin network. This enables the formation of active BCR microclusters at the cell surface, ultimately resulting in constitutive, BCR-driven NF-κB survival signaling. Moreover, we found that RHOA controlled endocytosis of the BCR and thereby the assembly of the endolysosomal My–T–BCR multiprotein complex, a central activator of NF-κB consisting of MYD88, Toll-like receptor 9, and the internalized BCR. The recurrent DLBCL-associated RHOA R5W mutation rendered RHOA constitutively active in its GTP-bound state and changed the conformation of the actin network from primarily filamentous actin to globular actin. This altered actin state led to an increase in BCR microcluster formation, amplification of NF-κB signaling, and resistance to inhibitors targeting chronic active BCR signaling. Hence, our study establishes RHOA and its mutant isoforms as critical regulators of oncogenic BCR signaling in DLBCL.LOEWE HessenDeutsche Forschungsgemeinschaft 501100001659Else Kröner-Fresenius-Stiftung 50110000304
Stability of bond clusters with a characteristic length scale for load distribution
No full textAbstract In biological materials, strong binding despite an applied load force is often based on clusters of dynamic bonds that share the load. Different macroscopic behaviors have been described depending on whether the load is shared locally or globally in the force-depended unbinding rate. Here we introduce and study a model in which the load is distributed over a characteristic length scale, introduced by an exponential decay. The model contains the local and global scenario as limiting cases and smoothly interpolates between them. We derive approximations in which some analytical results can be obtained. In particular, we derive rupture conditions and validate these with stochastic simulations. The model shows two main pathways for failure of the bond cluster, due to rupture of all bonds above a critical force and due to the formation of a critical crack, a large gap between closed bonds that spreads in both directions
The role of trust in wildlife damage response systems: One step towards coexistence between livestock farming and large carnivores?
No full textAbstract Wildlife damage to livestock and crops is the primary cause of conflict and a major barrier to human–wildlife coexistence across Europe and beyond. Data on such damages play a key role in understanding and shaping these conflicts. Policy responses have emphasised prevention and compensation to support extensive husbandry practices; however, these measures do not necessarily prevent conflicts, and damage management remains highly contested in some regions. Farmers' trust in the damage response system is decisive for coexistence strategies. Trust likely impacts whether affected farmers submit reliable depredation information, which is key to data validity. Trustful relations with authorities may also influence willingness to put in place livestock protection measures. Yet little is known about how choices in the damage response system affect trust. In this perspective, we argue that key pressure points impact three aspects of trust: (1) trust in institutional outcomes; (2) trust in institutional processes; and (3) interpersonal trust. Building on experience gathered in researching and implementing large carnivore management systems across the European Union (EU), and the exploration of case studies from five EU countries with contrasting wildlife governance systems and administrative processes, we discuss four aspects of the damage response system that have significant implications for trust: the role of the inspector; degree of centralisation and type of coordination; speed and predictability of response; and level of compensation. Beyond technical improvements, building trust should be a central focus of research and policy. The damage response system remains under‐examined and needs further empirical investigation and comparative work, including exploration of farmers' views. The professionalism, neutrality, and empathy of inspectors can foster positive farmer experiences and strengthen interpersonal trust in day‐to‐day wildlife management. Institutional trust can be reinforced through a well‐coordinated, fair compensation system with predictable responses within an agreed, ideally short, timeframe. Read the free Plain Language Summary for this article on the Journal blog.Read the free Plain Language Summary for this article on the Journal blog.Abstract Wildlife damage to livestock and crops is the primary cause of conflict and a major barrier to human–wildlife coexistence across Europe and beyond. Data on such damages play a key role in understanding and shaping these conflicts. Policy responses have emphasised prevention and compensation to support extensive husbandry practices; however, these measures do not necessarily prevent conflicts, and damage management remains highly contested in some regions. Farmers' trust in the damage response system is decisive for coexistence strategies. Trust likely impacts whether affected farmers submit reliable depredation information, which is key to data validity. Trustful relations with authorities may also influence willingness to put in place livestock protection measures. Yet little is known about how choices in the damage response system affect trust. In this perspective, we argue that key pressure points impact three aspects of trust: (1) trust in institutional outcomes; (2) trust in institutional processes; and (3) interpersonal trust. Building on experience gathered in researching and implementing large carnivore management systems across the European Union (EU), and the exploration of case studies from five EU countries with contrasting wildlife governance systems and administrative processes, we discuss four aspects of the damage response system that have significant implications for trust: the role of the inspector; degree of centralisation and type of coordination; speed and predictability of response; and level of compensation. Beyond technical improvements, building trust should be a central focus of research and policy. The damage response system remains under‐examined and needs further empirical investigation and comparative work, including exploration of farmers' views. The professionalism, neutrality, and empathy of inspectors can foster positive farmer experiences and strengthen interpersonal trust in day‐to‐day wildlife management. Institutional trust can be reinforced through a well‐coordinated, fair compensation system with predictable responses within an agreed, ideally short, timeframe. Read the free Plain Language Summary for this article on the Journal blog.Read the free Plain Language Summary for this article on the Journal blog
Artificial Intelligence–Assisted Error Detection in Complex Clinical Documentation: Leveraging Large Language Models to Enhance Patient Safety in Oncology
No full textPURPOSE In high-risk specialties such as oncology, errors in clinical documentation can have severe consequences, highlighting a need for enhanced safety checks. We therefore aimed to evaluate the capability of frontier large language models (LLMs) to identify and correct errors in complex clinical documentation in oncology. METHODS We conducted a two-phase evaluation. First, we assessed LLMs (GPT o4-mini and Gemini 2.5 Pro) on 1,000 synthetic clinical hematology/oncology vignettes with controlled errors, benchmarking against human expert data for error flag detection and sentence localization. Second, we evaluated advanced LLMs and a local LLM (Gemma 3 27B) against six clinicians in detecting single, predefined, and clinically relevant errors, such as wrong risk classifications or omission of critical medication within 90 synthetic discharge summaries from oncologic patients. RESULTS LLMs outperformed human benchmark in error flag and sentence localization tasks, with Gemini 2.5 Pro achieving top accuracies of 0.928 and 0.915, respectively. Results were robust across subgroups and scalable, with simultaneous processing of up to 50 vignettes. Within complex discharge summaries, Gemini 2.5 Pro and GPT o4-mini-high identified 97.8% and 87.8% of injected errors, respectively, substantially exceeding the 47.8% average detection rate of human specialists. Gemma 3 27B detected 35.6% of errors. Analysis of error detection overlap revealed a synergistic potential for hybrid human-artificial intelligence (AI) systems. CONCLUSION Frontier LLMs exhibit superior error‐detection capabilities and speed compared with both local models and human specialists, who are inherently time-constrained. Although synthetic data provide a controlled testbed, real-world evaluation across diverse errors and documentation styles remains critical. Advanced LLMs can serve as powerful assistants for clinical documentation reviews, substantially reducing the risk of oversight and clinician workload. Integrating LLM‐driven error flagging into electronic health record workflows offers a promising strategy for enhancing documentation accuracy, treatment quality, and patient safety in oncology