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Spatial evolution of a cachexia-promoting microenvironment in pancreatic cancer

Cell. 2026 Sep 29:S0092-8674(26)01081-0. doi: 10.1016/j.cell.2026.09.012. Online ahead of print.

ABSTRACT

Cachexia is a major cause of morbidity in pancreatic cancer, but the cellular circuitry linking tumor progression to systemic wasting remains incompletely understood. Integrating single-cell RNA sequencing, Xenium spatial transcriptomics, multiplex immunohistochemistry, bulk transcriptomics, and functional studies across human non-cachexia, pre-cachexia, and cachexia samples, together with mouse models, we define a cachexia-associated microenvironmental niche composed of SEMA4A+ tumor cells, AQP9+ macrophages, and LOXL2+ cancer-associated fibroblasts. Mechanistically, SEMA4A-associated signaling promotes bone morphogenetic protein-2 (BMP2)-dependent acquisition of an AQP9-associated macrophage phenotype, and macrophage-derived CXCL8 activates LOXL2+ fibroblasts. LOXL2+ fibroblasts reciprocally enhance tumor cell FOSL1/SEMA4A signaling through exosomal N-glycosylated LOXL2. Spatial analyses demonstrate progressive enrichment of this niche with cachexia severity and association with postoperative development of cachexia in previously non-cachectic patients. These findings provide a framework linking local tumor ecosystem dynamics to cachexia progression.

PMID:42810340 | DOI:10.1016/j.cell.2026.09.012

Mechanism of Action of Hedyotis diffusa Extract in a Rat Model of Acute Lung Injury Based on Transcriptomic Analysis

Biology (Basel). 2026 Sep 4;15(17):1549. doi: 10.3390/biology15171549.

ABSTRACT

OBJECTIVE: This study established a rat model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) to evaluate pathological damage, collagen deposition, inflammatory cytokine levels, and key gene/protein expression following Hedyotis diffusa water extract (HDWE) intervention. Combined with ultra-high-performance liquid chromatography-quadrupole Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS), transcriptomic analysis, and molecular simulation, this study identified the bioactive components of HDWE, evaluated their potential interactions with ALI-related targets, and explored the multi-omics-based protective mechanisms of HDWE.

METHODS: Thirty-six Sprague-Dawley (SD) rats were randomly divided into six groups: Control group, ALI group, DXMS group, HDWE-L group (100 mg/kg), HDWE-M group (200 mg/kg), and HDWE-H group (300 mg/kg). Hematoxylin and eosin (H&E) and Masson's trichrome staining were used to evaluate lung pathological changes and collagen deposition. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum tumor necrosis factor-α TNF-α interleukin-1β IL-1β, erleukin-6 (IL-6), and interleukin-10 (IL-10) levels. Transcriptomic analysis identified differentially expressed genes (DEGs), followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), receiver operating characteristic (ROC), and immune infiltration analyses. Quantitative real-time polymerase chain reaction (qRT-PCR) detected the mRNA expression levels of SPHK1, RELA, and NFKBIA. Immunohistochemistry evaluated the expression of eight hub targets, including endothelin-1 (EDN1), sphingosine kinase 1 (SPHK1), intercellular adhesion molecule 1 (ICAM1), interleukin-17 (IL-17), prostaglandin-endoperoxide synthase 2 (PTGS2/COX-2), NF-κB p65 (encoded by RELA), WT1-associated protein (WTAP), and myeloperoxidase (MPO). UHPLC-Q-Orbitrap HRMS characterized HDWE constituents. Molecular docking analysis was performed between 22 compounds and eight hub targets, followed by 100 ns molecular dynamics simulations and molecular mechanics-Poisson-Boltzmann surface area (MM/PBSA) binding free energy calculations for five core targets. Compared with the control group, the ALI group showed increased levels of TNF-α (86%), IL-1β (107%), and IL-6 (66%), accompanied by a 43% reduction in IL-10 and a 300% increase in lung collagen deposition. All HDWE doses alleviated inflammatory responses, with medium-dose HDWE showing the most pronounced effects. Specifically, medium-dose HDWE increased IL-10 levels by 52% and reduced IL-6, TNF-α, and IL-1β levels by 18%, 22%, and 11%, respectively. Transcriptomic analysis identified 2512 DEGs between the control group and ALI groups, 832 exclusive DEGs between the ALI group and HDWE-M groups, and 876 overlapping DEGs enriched in TNF, IL-17, and NF-κB signaling pathways. The eight-hub-gene diagnostic model achieved an area under the curve (AUC) of 0.969. RELA, SPHK1, and four other hub genes showed positive correlations with Th1, Th17, and neutrophil infiltration. In the ALI group, SPHK1, RELA, and NFKBIA mRNA expression levels were 1.30-, 0.96-, and 0.71-fold of those in the control group, respectively. Compared with the ALI group, high-dose HDWE treatment and low-dose HDWE treatment reduced SPHK1 expression to 0.62- and 0.57-fold, respectively, and increased NFKBIA expression to 1.68- and 1.58-fold, respectively. High-dose HDWE treatment reduced RELA expression to 0.43-fold. The expression levels of inflammation-related proteins were increased in the ALI group and were reduced after HDWE treatment. Twenty-two HDWE components were identified, 16 of which met the docking criteria. Asperulosidic acid exhibited favorable predicted binding affinities with all eight targets, with calculated binding free energies of -14.74, -14.92, -17.58, -23.04, and -16.10 kcal/mol for MPO, IL-17, NF-κB p65, PTGS2/COX-2, and SPHK1, respectively.

CONCLUSIONS: This study provides systematic in vivo pharmacodynamic and in silico component-target evidence regarding the protective effects of HDWE against LPS-induced ALI. HDWE treatment increased NFKBIA expression and reduced SPHK1, RELA, and multiple inflammatory protein levels, suggesting that HDWE may regulate the IL-17/NF-κB-associated inflammatory network, although direct causal relationships require further validation. Asperulosidic acid may represent a key bioactive component with broad target-binding potential. This study was limited by the use of an LPS-induced rat ALI model without gene knockout or target inhibitor validation; therefore, further functional experiments are required to confirm the proposed regulatory mechanisms.

PMID:42737981 | PMC:PMC13564518 | DOI:10.3390/biology15171549

Autoregression-Free Neural Operators for Time-Dependent PDEs

arXiv:2605.25413v1 Announce Type: cross Abstract: Neural operators learn mappings from function-dependent inputs to solutions, providing an effective framework for solving partial differential equations (PDEs). For time-dependent PDEs, existing methods typically perform long-horizon prediction through autoregressive rollout directly in high-dimensional physical field spaces, where each predicted state is recursively fed back as the input for the next step. Although effective for short-term prediction, this autoregressive rollout and the lack of continuous-time modeling lead to progressive error accumulation over long-horizon rollouts. In this work, we propose Autoregression-Free Neural Operators (AFNO), which map the time evolution of PDEs into a latent space and model continuous-time vector fields within it. AFNO uses flow matching to learn the latent vector field, thereby enabling continuous evolution over extended horizons, avoiding autoregressive rollout and capturing dynamics under varying parameter configurations through explicit conditioning on physical parameters. Theoretical analysis and extensive experiments on six PDEs demonstrate that AFNO improves long-horizon prediction stability and consistently reduces rollout errors compared with the baselines.

AgentArk: Distilling Multi-Agent Intelligence into a Single LLM Agent

arXiv:2602.03955v3 Announce Type: replace Abstract: While large language model (LLM) multi-agent systems achieve superior reasoning performance through iterative debate, practical deployment is limited by their high computational cost and error propagation. This paper proposes AgentArk, a novel framework to distill multi-agent dynamics into the weights of a single model, effectively transforming explicit test-time interactions into implicit model capabilities. This equips a single agent with the intelligence of multi-agent systems while remaining computationally efficient. Specifically, we investigate three hierarchical distillation strategies across various models, tasks, scaling, and scenarios: reasoning-enhanced fine-tuning; trajectory-based augmentation; and process-aware distillation. By shifting the burden of computation from inference to training, the distilled models preserve the efficiency of one agent while exhibiting strong reasoning and self-correction performance of multiple agents. They further demonstrate enhanced robustness and generalization across diverse reasoning tasks. We hope this work can shed light on future research on efficient and robust multi-agent development. Our code is at https://github.com/AIFrontierLab/AgentArk.

Marker-Based 3D Reconstruction of Aggregates with a Comparative Analysis of 2D and 3D Morphologies

arXiv:2603.12667v1 Announce Type: cross Abstract: Aggregates, serving as the main skeleton in assemblies of construction materials, are important functional components in various building and transportation infrastructures. They can be used in unbound layer applications, e.g. pavement base and railroad ballast, bound applications of cement concrete and asphalt concrete, and as riprap and large-sized primary crushed rocks. Information on the size and shape or morphology of aggregates can greatly facilitate the Quality Assurance/Quality Control (QA/QC) process by providing insights of aggregate behavior during composition and packing. A full 3D characterization of aggregate particle morphology is difficult both during production in a quarry and at a construction site. Many aggregate imaging approaches have been developed to quantify the particle morphology by computer vision, including 2D image-based approaches that analyze particle silhouettes and 3D scanning-based methods that require expensive devices such as 3D laser scanners or X-Ray Computed Tomography (CT) equipment. This paper presents a flexible and cost-effective photogrammetry-based approach for the 3D reconstruction of aggregate particles. The proposed approach follows a marker-based design that enables background suppression, point cloud stitching, and scale referencing to obtain high-quality aggregate models. The accuracy of the reconstruction results was validated against ground-truth for selected aggregate samples. Comparative analyses were conducted on 2D and 3D morphological properties of the selected samples. Significant differences were found between the 2D and 3D statistics. Based on the presented approach, 3D shape information of aggregates can be obtained easily and at a low cost, thus allowing convenient aggregate inspection, data collection, and 3D morphological analysis.

Long-Short Term Agents for Pure-Vision Bronchoscopy Robotic Autonomy

arXiv:2603.07909v1 Announce Type: cross Abstract: Accurate intraoperative navigation is essential for robot-assisted endoluminal intervention, but remains difficult because of limited endoscopic field of view and dynamic artifacts. Existing navigation platforms often rely on external localization technologies, such as electromagnetic tracking or shape sensing, which increase hardware complexity and remain vulnerable to intraoperative anatomical mismatch. We present a vision-only autonomy framework that performs long-horizon bronchoscopic navigation using preoperative CT-derived virtual targets and live endoscopic video, without external tracking during navigation. The framework uses hierarchical long-short agents: a short-term reactive agent for continuous low-latency motion control, and a long-term strategic agent for decision support at anatomically ambiguous points. When their recommendations conflict, a world-model critic predicts future visual states for candidate actions and selects the action whose predicted state best matches the target view. We evaluated the system in a high-fidelity airway phantom, three ex vivo porcine lungs, and a live porcine model. The system reached all planned segmental targets in the phantom, maintained 80\% success to the eighth generation ex vivo, and achieved in vivo navigation performance comparable to the expert bronchoscopist. These results support the preclinical feasibility of sensor-free autonomous bronchoscopic navigation.

TikArt: Aperture-Guided Observation for Fine-Grained Visual Reasoning via Reinforcement Learning

arXiv:2602.14482v1 Announce Type: cross Abstract: We address fine-grained visual reasoning in multimodal large language models (MLLMs), where key evidence may reside in tiny objects, cluttered regions, or subtle markings that are lost under a single global image encoding. We introduce TikArt (Thinking Aperture), an aperture-guided agent that casts multi-step vision-language reasoning as a decision process over regions of interest. TikArt follows a Think-Aperture-Observe loop, alternating between language generation and two aperture actions: Zoom extracts rectangular crops, while Segment invokes SAM2 to obtain mask-based crops for irregular targets. After every action, the model must produce an explicit observation, turning local visual cues into persistent linguistic memory. Built on Qwen3-VL-8B, TikArt optimizes its reasoning policy with AGRPO, a GRPO-style reinforcement learning algorithm with a two-stage curriculum: it warms up segmentation actions and then jointly optimizes visual math, fine-grained VQA, and segmentation, using rewards that couple task success with purposeful aperture use. Experiments on V*, HR-Bench-4K/8K, MME-RealWorld-Lite, MMStar, RefCOCO, and ReasonSeg show consistent gains over the backbone and yield interpretable aperture trajectories for high-resolution reasoning.
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