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Structural insights into measles virus RNA synthesis regulation and pan-paramyxoviral polymerase inhibition by ERDRP-0519
Nonsegmented negative-sense RNA viruses (nsNSVs) rely on a multifunctional RNA-dependent RNA polymerase (RdRP) complex for transcription and replication. In measles virus (MeV), the nonstructural protein C has long been implicated in regulating RNA synthesis, yet its precise role remains unclear. Here, we show that the MeV C protein directly associates with the RdRP complex. Using cryoelectron microscopy, we determined atomic-resolution structures of the MeV polymerase with and without C, revealing that C binding stabilizes the C-terminal region of L and locks the complex into a replication-competent elongation state. Biochemical data further show that C promotes N protein recruitment, enhancing polymerase processivity through facilitating encapsidation during replication. Additionally, we also resolved high-resolution structures of MeV and Nipah virus (NiV) polymerases bound to ERDRP-0519, an orally available morbillivirus inhibitor. Unexpectedly, the compound occupies an allosteric pocket within the RdRp domain rather than the previously predicted PRNTase domain, overlapping conserved resistance sites. This binding induces conformational changes in palm subdomain, blocking RNA template and nucleotide engagement, thereby halting RNA synthesis. These findings uncover distinct regulatory and inhibitory mechanisms in paramyxovirus polymerases and provide a structural framework for the rational design of broad-spectrum antivirals targeting MeV, NiV, and potentially other clinically relevant nsNSVs.
Hybrid framework for robust runoff forecasting via decomposition and machine learning
Microvesicle release drives cycles of mitophagy flux disruption and inflammatory amplification in sepsis-induced myocardial dysfunction
Sepsis-induced myocardial dysfunction strongly contributes to high mortality in patients with sepsis by exacerbating systemic organ failure; however, the onset and molecular mechanisms driving this vicious cycle remain unclear. Here, we revealed that DRP1-mediated mitochondrial fission and excessive reactive oxygen species (ROS) accumulation are central to the disruption of mitophagy flux and triggering of inflammatory cascades. Using cecal ligation and puncture mice and lipopolysaccharide-treated HL-1 cell models, combined with advanced imaging and molecular analyses, we demonstrated that elevated ROS activates the RIP1/RIP3 pathway, impairing mitophagy flux and promoting the release of microvesicles containing mitochondrial inner membrane components and mitochondrial DNA. These microvesicles amplify inflammatory responses through the cGAS–STING and RIP1/RIP3 pathways, driving the production of damage- and pathogen-associated molecular patterns. This study highlights two interlinked vicious cycles, mitophagy flux disruption and damage- and pathogen-associated molecular pattern amplification, as critical drivers of sepsis-induced myocardial injury, providing therapeutic targets for mitigating inflammatory damage and improving clinical outcomes in patients with sepsis.
Carbon dot based topical application for therapy of phosphorus oxide-induced cutaneous burns
Hyperactive Rac converts sublethal to lethal trogocytosis in vivo
The small GTPase Rac is an essential regulator of cell shape, migration, macropinocytosis, and phagocytosis. We found that expression of constitutively active Rac G12V is sufficient to cause a few migratory cells called border cells to cannibalize neighboring nurse cells in the Drosophila ovary. Building on that insight, we engineered mammalian Rac-enhanced chimeric-antigen-receptor macrophages (RaceCAR-Ms) to avidly engulf and kill cancer cells. Here, we investigate the cellular and molecular mechanisms by which border cells efficiently kill the much larger nurse cells. Surprisingly, wild type border cells normally nibble on nurse cells as they migrate between them, and Rac G12V causes border cells to take larger, lethal bites. These larger bites trigger rapid germline shrinkage, nuclear damage, and caspase activation, which spreads through the nurse cell syncytium. Then, many somatic follicle cells join in to engulf the dying germline. Rac and the engulfment receptor Draper are critical for both sublethal and lethal nibbling (trogocytosis). Using clonal analysis, we show small groups of follicle cells expressing Rac G12V induced caspase activation in neighboring follicle cells while larger Rac G12V clones were required to cause germline killing. Increasing Draper expression or JNK activity in border cells also caused germline death, in a Rac-independent manner, suggesting that border cells can be activated to kill through multiple mechanisms. The series of events elucidated here reveals how hyperactivated Rac expressed in a few cells can trigger destruction of a much larger mass.
An snRNA-seq aging clock for the fruit fly head sheds light on sex-biased aging
Reply to Alexandre et al.: Insensitivity of the Δ <sup>′17</sup> O value of equisetum to atmospheric relative humidity
Correction: Association between TyG-BMI and early-onset hypertension: evidence from NHANES
Oocyte-inspired universal whole-cell vaccines against tumor heterogeneity
Tumor heterogeneity poses a major challenge to tumor therapy due to the expression of unique, poorly recognized immunogenic proteins driven by environmental stress. The broad antigenic repertoire of cell-based vaccines, particularly their inclusion of tumor-specific antigens, holds substantial promise for the prevention and treatment of heterogeneous tumors. However, antigen loss during vaccine preparation and insufficient immune activation remain critical challenges for their clinical application. Inspired by the zona pellucida structure of oocytes, an extracellular protective barrier, we developed biomimetic whole-tumor cell vaccines with tunable mechanical properties that preserve the complete repertoire of whole-cell immunogenic proteins. The biomimetic shells optimize cellular mechanics to facilitate phagocytosis and antigen processing, while the cryo-inactivation strategically disrupted intracellular architecture to enhance antigen presentation efficiency. The biomimetic vaccines effectively preserve patient-specific antigen profiles, thereby enabling the generation of tailored immune responses for individualized therapy. Building on the preserved whole-cell antigen pools, we further developed universal vaccines from heterogeneous tumor cells shaped under microenvironmental selective pressures. These vaccines exhibit poly-valent efficacy against tumor heterogeneity, offering considerable potential for both therapeutic and preventive application.
Germline pathogenic variant spectrum and prevalence among colorectal cancer patients undergoing multigene panel testing in Kazakhstan
Building courage, strength, and knowledge: Mindfulness training reduces psychological threat and increases engagement in college physics
Many college students experience introductory physics as psychologically threatening. In a preregistered RCT, we applied the biopsychosocial model of challenge-threat to describe patterns of threat in introductory physics and test whether a 5-d mindfulness training could reduce threat and increase engagement among undergraduates. Course-wide surveys (N = 954) screened students for the RCT and revealed roughly half of students experience psychological threat. Students identified with systemically excluded groups were more likely to experience psychological threat while systemically advantaged students were more likely to experience psychological challenge in their introductory physics course. In the RCT (N = 149), mindfulness training reduced psychological threat and fostered greater engagement in introductory physics, and, consistent with our theory of change, mindfulness training was associated with greater physics engagement through reductions in threat. The results demonstrate that mindfulness can help students manage stress more effectively by reducing psychological threat and fostering engagement in contexts like introductory physics.
Pangenome-wide identification of chloroplast RNA splicing and ribosome maturation (CRM) genes in eight Pyrus genomes indicated their involvement in multiple stresses
Thermodynamically consistent machine learning model for excess Gibbs energy
Abstract The excess Gibbs energy plays a central role in chemical engineering and chemistry, providing a basis for modeling thermodynamic properties of liquid mixtures. Predicting the excess Gibbs energy of multi-component mixtures solely from molecular structures is a long-standing challenge. We address this challenge with HANNA, a flexible machine learning model for excess Gibbs energy that integrates physical laws as hard constraints, guaranteeing thermodynamically consistent predictions. HANNA is trained on experimental data for vapor-liquid equilibria, liquid-liquid equilibria, activity coefficients at infinite dilution, and excess enthalpies in binary mixtures. The end-to-end training on liquid-liquid equilibrium data is facilitated by a surrogate solver. A geometric projection method enables robust extrapolations to multi-component mixtures. We demonstrate that HANNA delivers accurate predictions, while providing a substantially broader domain of applicability than state-of-the-art benchmark methods. The trained model and corresponding code are openly available, and an interactive interface is provided on our website, MLPROP.
Niche-dependent modular regulation of the stem cell transcriptome separates cell identity and potential
Adult stem cells maintain tissue homeostasis, yet are themselves vulnerable to loss. One common mechanism to replace lost stem cells is dedifferentiation, in which progeny revert to stem cell identity. It is a paradox how stem cells and progeny retain the same stem cell potential while exhibiting distinct current identities of self-renewal, differentiation, and dedifferentiation. Here, we show that the Drosophila male germline lineage solves this paradox via two parallel and complementary mechanisms to separate potential and identity. First, differentiating progeny maintain stem cell potency by inheriting perdurant stem cell mRNAs without actively transcribing them. Second, two known niche signals (Bmp and Jak-Stat) activate distinct sets of targets, defining three identities (self-renewal, differentiation, and dedifferentiation) based on the combination of their on/off states. Together, this study reveals how a pool of dedifferentiation-competent progeny is maintained to regenerate stem cells as needed without resulting in stem cell overproduction and resolves the puzzle of why most stem cell systems require multiple independent niche signals.
Evaluation of systemic and mucosal immune responses in Nile tilapia following intraperitoneal and immersion vaccination with inactivated tilapia lake virus (TiLV) vaccine
Direct observation of organic molecules in asteroid ryugu revealed by high-resolution atomic force microscope
Abstract A diverse variety of organic matter exists in space. Since these extraterrestrial organic materials preserve chemical information from the early solar system, their identification has been extensively studied. However, detailed structural information has remained limited. Here we investigate organic matter from the carbonaceous asteroid Ryugu using a high-resolution atomic force microscope (AFM). We directly resolve the chemical structures of individual organic molecules from the asteroid. We find a wide variety of polycyclic aromatic hydrocarbons (PAHs), many of which are unexpectedly large in size. The largest one is composed of approximately 100 fused rings, significantly larger than the extraterrestrial PAHs identified in previous ensemble-level analyses. These PAHs exhibit non-planar structures incorporating five-, six-, seven-, and even eight-membered rings. Such complex structures can be resolved in detail only through single-molecule AFM analysis.
Hydraulic stress limits thermal acclimation in trees under chronic drought
The capacity of trees to withstand intensifying hot drought events depends on the coordination between hydraulic safety and leaf thermoregulation, yet the limits of this coordination under chronic stress remain poorly understood. Here, we show that 5 y of chronic soil moisture limitation fundamentally constrains the capacity of leaves to maintain adequate thermoregulation. Focusing on two temperate tree species with contrasting water-use strategies, European beech ( Fagus sylvatica ) and downy oak ( Quercus pubescens ), which were subjected to a 5-y manipulation of soil moisture and air temperature, we tested how acclimation influences leaf thermoregulation, hydraulic safety margins (HSMs), thermal safety margins (TSMs), and leaf scorching. Under sustained heating with ample soil water availability, both species acclimated to maintain stable leaf temperature and positive TSMs despite warmer conditions, demonstrating that thermal acclimation is possible without hydraulic stress. By contrast, chronic soil drought narrowed HSMs and weakened evaporative cooling, reducing leaf thermoregulation capacity. When drought and heat co-occurred, stomatal closure triggered a runaway feedback loop: Impaired water transport led to loss of cooling, causing breaching of critical thermal thresholds. These events coincided with failures of photosystem II and scorching in drought-vulnerable beech, linking drought-induced stomatal limitation directly to thermal injury. Our results reveal that oak and beech can acclimate to warming alone, but not to simultaneous heat and drought, which together drive a hydraulic–thermal cascade exceeding both safety margins. This interaction sets fundamental limits on the resilience of temperate forests to future hot droughts.