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Inositol Metabolism Modulates Inflammatory Injury in Acute Pancreatitis via the ISYNA1-NETs Axis

J Inflamm Res. 2026 Sep 22;19:606503. doi: 10.2147/JIR.S606503. eCollection 2026.

ABSTRACT

BACKGROUND: Neutrophil extracellular traps (NETs) were key factors mediating inflammatory injury in acute pancreatitis (AP). To this end, there was an urgent need to identify precise and effective therapeutic targets that modulate NETs formation, providing new ideas for the prevention and treatment of AP pancreatitis injury.

GAP: To address this gap, we investigated the potential involvement of the myo-inositol metabolism in modulating NETs and inflammatory damage during AP.

METHODS: Multi-omics analysis identified myo-inositol metabolism as critical. We then established the in vitro NETs model using phorbol-12-myristate-13-acetate (PMA) to investigate the role and regulatory mechanism of inositol-3-phosphate synthase 1 (ISYNA1) on NETs formation. Finally, the findings were validated in the classic AP mouse model to verify the correlation between myo-inositol metabolism and AP pathogenesis.

RESULTS: Multiple omics analyses showed that the myo-inositol metabolic pathway is the most significant, and the key enzyme ISYNA1 involved in myo-inositol synthesis was significantly reduced. ISYNA1 was significantly downregulated in both the in vitro NETs model and in neutrophils infiltrating the pancreatic tissue of AP mice. Meanwhile, exogenous supplementation of ISYNA1 or myo-inositol significantly inhibited the NETs formation in vitro and inflammatory injury in AP mice. Mechanistically, downregulation of ISYNA1 led to reduced myo-inositol synthesis, thereby promoting NETs formation via modulation of the PI3K/AKT pathway.

CONCLUSION: ISYNA1 and myo-inositol metabolism were among the key links that regulated NETs formation and inflammatory injury in AP. Therefore, enhancing ISYNA1 and myo-inositol metabolism might serve as a potential intervention target for treating acute organ injury in AP.

PMID:42801157 | PMC:PMC13615823 | DOI:10.2147/JIR.S606503

How Good Are Frontier Models at Physics? Expert Re-Grading Reveals Broken Evaluations and Near-Saturation of Leading Benchmarks

arXiv:2609.13009v1 Announce Type: new Abstract: Low reported scores on leading physics benchmarks, including those featured in the Artificial Analysis Intelligence Index (2026), suggest that frontier language models still struggle with advanced physics, a demanding test of their scientific reasoning and quantitative problem-solving abilities. Yet this impression does not always align with domain experts' experiences using these models in their work. We revisit these reported findings by evaluating frontier models on six widely used physics benchmarks and auditing them with experts, focusing on text-only problems with verifiable final answers. For each subfield of physics, faculty and graduate researchers with relevant expertise carefully review problem statements, reference solutions, and model responses to distinguish genuine model errors from grader errors, incorrect reference solutions, and ambiguous or underspecified questions. Most audited cases initially evaluated as incorrect reflect these benchmarking issues rather than errors in the models' physics reasoning. We then ask experts to address these benchmarking issues by correcting erroneous reference solutions and repairing or excluding flawed questions. We find that GPT-5.6-Sol's measured mean@4 rises from 47.3% to 78.7% on HLE-Physics and from 61.0% to 87.2% on CMT-Benchmark, while its corrected pass@4 reaches 94.4% on the 54 retained CritPt challenges. Corrected scores are computed on the retained evaluation subsets following expert review. Scores on the audited subsets of UGPhysics, PRISM-Physics, and PHYBench also rise substantially after correction. These findings suggest that current benchmarks substantially understate frontier models' ability to solve well-posed physics problems. Near-saturation on these closed-ended tasks highlights the need for more demanding, expert-validated evaluations.

SCOPE-OPSD: Fisher-Conditioned Privileged Subspaces for On-Policy Self-Distillation

arXiv:2609.12579v1 Announce Type: cross Abstract: On-policy self-distillation (OPSD) scores student-generated prefixes with a solution-conditioned self-teacher, yet transfers supervision only through next-token probabilities. We ask whether the aligned final-layer discrepancy offers a useful second channel, and how to test that channel without confusing its geometry with auxiliary strength. SCOPE-OPSD projects the privileged teacher-student residual onto a frozen rank-64 factor estimated from residual covariance and language-model-head Fisher sensitivity. It reuses the forwards already required by OPSD and adds neither rollouts nor inference-time modules. A matched Random control preserves the structured factor's rank and nonzero spectrum and uses per-arm gradient-RMS calibration, isolating the effect of the data-dependent orientation. Across the complete 25/50/75/100-step trajectories for Qwen3-1.7B, 4B, and 8B, Structured is never below Pure OPSD, with strict gains in 11 of the 12 model-checkpoint combinations and an exact tie at 4B step 25. Structured also exceeds matched Random in 10 of the 12 combinations. At step 75 on Qwen3-1.7B, Structured exceeds matched Random by 1.39 Macro Avg@12 points in each of two independent training reruns. A cross-fitted diagnostic also shows 4.40 times greater held-out privileged-gap capture than the matched random orientation. The results support a compact, Fisher-conditioned privileged subspace for short-budget OPSD.

Impact of LLM-supported patient education on patient perspectives and patient-reported outcomes: a mixed-methods systematic review

npj Digital Medicine, Published online: 10 September 2026; doi:10.1038/s41746-026-03228-7

Impact of LLM-supported patient education on patient perspectives and patient-reported outcomes: a mixed-methods systematic review

Semigroup-JEPA: Latent Dynamics Consistency for Zero-Shot Physics Generalization

arXiv:2609.10464v1 Announce Type: cross Abstract: Joint-Embedding Predictive Architecture (JEPA) world models learn a compact latent representation of the world that supports prediction and planning, but their capability to learn physics and generate physically realistic dynamics remains hitherto untested. In this work, we introduce SemiGroup-JEPA (SG-JEPA), which extends the LeWorldModel framework by supplying the parameter governing the physics to the temporal model via action-conditioning and jointly training an encoder and predictor through an autoregressive latent rollout. To evaluate the model's ability to generalize out of distribution, we design dynamical tasks under different gravitational fields that, despite obeying the same physical law, exhibit qualitatively different dynamics, ranging from floating motion in weak gravitational fields to rapid bouncing in strong ones. In contrast to DINO-WM, SG-JEPA reduces open-loop prediction error by up to 2 times on two-dimensional datasets, and increases control success rate up to 2.5 times for three-dimensional robotic datasets, for which we train independent diffusion policies. To explain this advantage, we develop a linear feature model that separates local law-conditioned error from its recursive amplification under rollout. Guided by this model, we find that back-propagating the multi-step rollout loss into the representation trains the encoder to keep the features that the predictor can carry forward, and that those are the features the dynamics depend on, so most of the gain comes from the encoder learning better features rather than from the predictor learning better dynamics. See project page at https://sg-jepa.github.io.

MADS: Multi-Agent Dialogue Simulation for Diverse Persuasion Data Generation

arXiv:2510.05124v3 Announce Type: replace-cross Abstract: We propose MADS (Multi-Agent Dialogue Simulation), a scalable framework for generating persuasive multi-turn dialogues via agent self-play. MADS employs three coordinated agents: User Agents designed to simulate diverse persona-driven behaviors by leveraging personality signifiers such as Zodiac Signs and MBTI types, a Dialog Agent executing task-oriented persuasion strategies and an Optimization Agent evaluating and refining dialogue outcomes. We further validate its effectiveness through users' Chain-of-Attitude (CoA) modeling and dedicated LLMs' persuasion assessment. This approach enables low-cost generation of training data without human annotation, addressing key industry challenges such as lack of user data, cold-start evaluation difficulties, and prompt inefficiency. Applied to a real-world marketing scenario, MADS significantly improved the persuasion capacity of small LLMs, increasing the organic traffic conversion rate by 22.4% (from 1.83% to 2.24%) , demonstrating clear business value.

Transmembrane glycoprotein BSG serves a dual role as a prognostic and immunological modulator in the tumor microenvironment of lung adenocarcinoma

Transl Oncol. 2026 Sep 8;73:102990. doi: 10.1016/j.tranon.2026.102990. Online ahead of print.

ABSTRACT

BACKGROUND: Lung adenocarcinoma (LUAD) is a predominant and lethal subtype of non-small cell lung cancer, with a lack of reliable prognostic biomarkers to guide clinical management. Basigin (BSG) has been implicated in tumor progression across multiple cancers, yet its expression pattern, prognostic significance, and underlying mechanisms in LUAD remain incompletely elucidated.

METHODS: We integrated multi-omics data from TCGA, GTEx, CCLE, and GEO databases to analyze BSG expression profiles. Clinical correlations were assessed via Kruskal-Wallis tests. Prognostic value was determined using Kaplan-Meier survival analysis, univariate/multivariate Cox regression, and nomogram construction with calibration curves. Functional enrichment (GO/KEGG) and immune infiltration analyses were performed to explore BSG-related mechanisms, followed by immunohistochemical (IHC) validation in A549 cells and clinical LUAD tissue microarrays.

RESULTS: BSG was significantly upregulated in LUAD tissues versus normal/paired adjacent tissues, correlating with advanced T/N/pathologic stages. High BSG expression predicted worse survival outcomes in TCGA-LUAD, which was validated in GEO datasets. Multivariate Cox regression identified BSG as an independent prognostic factor, with a well-calibrated nomogram for survival prediction. Functional exploration indicated that BSG mainly participated in tumor-associated and immunological pathways. Immune infiltration analysis indicated that BSG was significantly correlated with the infiltration of various immune cells. Moreover, BSG exhibited a strong association with immune checkpoint proteins, chemokines, chemokine receptors, and MHC genes. IHC further confirmed its cytoplasmic/membranous localization and prognostic relevance.

CONCLUSION: BSG serves as an independent prognostic biomarker and potential therapeutic target in LUAD, shedding light on its regulatory roles in tumor progression and immune microenvironment remodeling.

PMID:42710246 | DOI:10.1016/j.tranon.2026.102990

Transmembrane glycoprotein BSG serves a dual role as a prognostic and immunological modulator in the tumor microenvironment of lung adenocarcinoma

Transl Oncol. 2026 Sep 8;73:102990. doi: 10.1016/j.tranon.2026.102990. Online ahead of print.

ABSTRACT

BACKGROUND: Lung adenocarcinoma (LUAD) is a predominant and lethal subtype of non-small cell lung cancer, with a lack of reliable prognostic biomarkers to guide clinical management. Basigin (BSG) has been implicated in tumor progression across multiple cancers, yet its expression pattern, prognostic significance, and underlying mechanisms in LUAD remain incompletely elucidated.

METHODS: We integrated multi-omics data from TCGA, GTEx, CCLE, and GEO databases to analyze BSG expression profiles. Clinical correlations were assessed via Kruskal-Wallis tests. Prognostic value was determined using Kaplan-Meier survival analysis, univariate/multivariate Cox regression, and nomogram construction with calibration curves. Functional enrichment (GO/KEGG) and immune infiltration analyses were performed to explore BSG-related mechanisms, followed by immunohistochemical (IHC) validation in A549 cells and clinical LUAD tissue microarrays.

RESULTS: BSG was significantly upregulated in LUAD tissues versus normal/paired adjacent tissues, correlating with advanced T/N/pathologic stages. High BSG expression predicted worse survival outcomes in TCGA-LUAD, which was validated in GEO datasets. Multivariate Cox regression identified BSG as an independent prognostic factor, with a well-calibrated nomogram for survival prediction. Functional exploration indicated that BSG mainly participated in tumor-associated and immunological pathways. Immune infiltration analysis indicated that BSG was significantly correlated with the infiltration of various immune cells. Moreover, BSG exhibited a strong association with immune checkpoint proteins, chemokines, chemokine receptors, and MHC genes. IHC further confirmed its cytoplasmic/membranous localization and prognostic relevance.

CONCLUSION: BSG serves as an independent prognostic biomarker and potential therapeutic target in LUAD, shedding light on its regulatory roles in tumor progression and immune microenvironment remodeling.

PMID:42710246 | DOI:10.1016/j.tranon.2026.102990

ITGA5 promotes homologous recombination mediated radioresistance in esophageal squamous cell carcinoma by upregulating RAD51AP1 expression

Oncogene, Published online: 04 September 2026; doi:10.1038/s41388-026-03966-8

ITGA5 promotes homologous recombination mediated radioresistance in esophageal squamous cell carcinoma by upregulating RAD51AP1 expression

Genomics and social practices at Mogou and other Gansu sites during prehistoric trans-Eurasian exchange

Ancient DNA from 149 individuals at 11 sites in Gansu, China, dated to around 4,700–3,000 years ago, reveals human population history during early transcontinental exchanges of agriculture and technology, as well as contemporary social practices, at the large Mogou cemetery.

Towards end-to-end LLM-based censoring-aware survival analysis

arXiv:2605.25399v1 Announce Type: new Abstract: Objective: Survival analysis is central to medical prediction, yet large language models (LLMs) are rarely used as end-to-end survival models because censoring prevents straightforward supervised fine-tuning. Here we present LLMSurvival, a framework that enables censoring-aware survival analysis with unmodified LLMs operating directly on tabular clinical data. Materials and Methods: LLMSurvival reformulates time-to-event prediction as pairwise ranking among comparable subjects, and derives test-time risk by aggregating comparisons against anchor individuals from the training cohort. Results: Across two clinical tasks (ICU mortality prediction in MIMIC-IV and fragility fracture prediction in a NewYork-Presbyterian/Weill Cornell Medicine cohort), LLMSurvival improves overall concordance over Cox proportional hazards modeling by 3.1% for ICU mortality and 0.5% for fracture risk, 2.1% on average for ICU mortality and 2.8% for fracture risk over three established deep learning survival models. Discussion: The results show that survival modeling with censoring can be made compatible with LLM fine-tuning through comparison-based reformulation. The framework demonstrates high portability and superior performance over expert curated scores like SAPS-II and FRAX scores across diverse clinical context. Furthermore, the framework supports local deployment, as compact, publicly available base models provide sufficient performance. Conclusion: The LLMSurvival framework serves as a proof of concept for an integrated, censoring-conscious approach to survival analysis via LLMs.

Agent World Model: Infinity Synthetic Environments for Agentic Reinforcement Learning

arXiv:2602.10090v3 Announce Type: replace Abstract: Recent advances in large language model (LLM) have empowered autonomous agents to perform multi-turn interactions with tools and environments. However, scaling such agent training is limited by the lack of diverse and reliable environments. In this paper, we propose Agent World Model (AWM), a fully synthetic environment generation pipeline. Using this pipeline, we scale to 1,000 environments covering everyday scenarios, in which agents can interact with rich toolsets and obtain high-quality observations. Notably, these environments are code-driven and backed by databases, providing more reliable and consistent state transitions than environments simulated by LLMs. Moreover, they enable more efficient agent interaction compared with collecting trajectories from realistic environments. To demonstrate the effectiveness of this resource, we perform large-scale reinforcement learning for multi-turn tool-use agents. Thanks to the fully executable environments and accessible database states, we can also design reliable reward functions. Experiments on three benchmarks show that training exclusively in synthetic environments, rather than benchmark-specific ones, yields strong out-of-distribution generalization. The code is available at https://github.com/Snowflake-Labs/agent-world-model.

Safety in Embodied AI: A Survey of Risks, Attacks, and Defenses

arXiv:2605.02900v2 Announce Type: replace-cross Abstract: Embodied Artificial Intelligence (Embodied AI) integrates perception, cognition, planning, and interaction into agents that operate in open-world, safety-critical environments. As these systems gain autonomy and enter domains such as transportation, healthcare, and industrial or assistive robotics, ensuring their safety becomes both technically challenging and socially indispensable. Unlike digital AI systems, embodied agents must act under uncertain sensing, incomplete knowledge, and dynamic human-robot interactions, where failures can directly lead to physical harm. This survey provides a comprehensive and structured review of safety research in embodied AI, examining attacks and defenses across the full embodied pipeline, from perception and cognition to planning, action and interaction, and agentic system. We introduce a multi-level taxonomy that unifies fragmented lines of work and connects embodied-specific safety findings with broader advances in vision, language, and multimodal foundation models. Our review synthesizes insights from over 500 papers spanning adversarial, backdoor, jailbreak, and hardware-level attacks; attack detection, safe training and robust inference; and risk-aware human-agent interaction. This analysis reveals several overlooked challenges, including the fragility of multimodal perception fusion, the instability of planning under jailbreak attacks, and the trustworthiness of human-agent interaction in open-ended scenarios. By organizing the field into a coherent framework and identifying critical research gaps, this survey provides a roadmap for building embodied agents that are not only capable and autonomous but also safe, robust, and reliable in real-world deployment.

FCGR2B (+) Macrophages as a Critical Node Linking Ferroptosis and Immunosuppression: A Multiomics Framework for Prognosis and Therapy in High-Grade Serous Ovarian Cancer

Hum Mutat. 2026 Apr 6;2026:8027584. doi: 10.1155/humu/8027584. eCollection 2026.

ABSTRACT

BACKGROUND: High-grade serous ovarian cancer (HGSOC) is characterized by a complex tumor microenvironment and poor prognosis, yet the roles of specific tumor-associated macrophages (TAMs) subpopulations in driving disease progression remain elusive.

METHODS: This study evaluated the prognostic relevance of FCGR2B in HGSOC. Single-cell RNA sequencing identified FCGR2B + TAMs as a distinct macrophage subpopulation with unique transcriptional features. Integrative analyses combining single-cell and bulk differentially expressed genes, macrophage-associated modules, and ferroptosis-related gene sets identified 26 candidate prognostic genes, from which a four-gene signature (CRYAB, PLAUR, EREG, and C5AR1) was derived to construct the prognostic risk model. The model was validated in an independent cohort. Immune infiltration, single-cell trajectory, copy number variation, and drug-gene associations were analyzed to explore the molecular and therapeutic implications of risk stratification.

RESULTS: HGSOC patients classified as high risk exhibited poorer survival outcomes, increased infiltration of M2-like macrophages, elevated expression of immune checkpoints, and enrichment of immune- and ferroptosis-related pathways. Trajectory and copy number variation analyses revealed stage-specific gene expression patterns and amplification-associated regulation. Drug-gene association analyses further suggested that high-risk patients may be more responsive to targeted therapies and proteasome inhibitors, whereas low-risk patients may benefit from conventional chemotherapy.

CONCLUSION: FCGR2B + TAMs are closely linked to HGSOC progression, and the proposed prognostic model based on FCGR2B + TAMs provides predictive value and potential therapeutic insights for patient stratification.

PMID:41953398 | PMC:PMC13054137 | DOI:10.1155/humu/8027584

Enhancing behavioral nudges with large language model-based iterative personalization: A field experiment on electricity and hot-water conservation

arXiv:2604.03881v1 Announce Type: cross Abstract: Nudging is widely used to promote behavioral change, but its effectiveness is often limited when recipients must repeatedly translate feedback into workable next steps under changing circumstances. Large language models (LLMs) may help reduce part of this cognitive work by generating personalized guidance and updating it iteratively across intervention rounds. We developed an LLM agent for iterative personalization and tested it in a three-arm randomized experiment among 233 university residents in China, using daily electricity and shower hot-water conservation as objectively measured cases differing in friction. LLM-personalized nudges (T2) produced the largest conservation effects, while image-enhanced conventional nudges (T1) and text-based conventional nudges (C) showed similar outcomes (omnibus p = 0.009). Relative to C, T2 reduced electricity consumption by 0.56 kWh per room-day (p = 0.014), corresponding to an 18.3 percentage-point higher adjusted saving rate. This advantage emerged within the first two intervention rounds, alongside iterative updating of personalized guidance, and persisted thereafter. Hot-water outcomes followed the same direction but were smaller, less precisely estimated, and attenuated over time, consistent with stronger friction in this domain. LLM-personalized nudges emphasized prospective and context-specific guidance and were associated with higher participant engagement. This study provides field evidence that LLM-based iterative personalization can enhance behavioral nudging, with behavioral friction as a potential boundary condition. Larger trials and extension to more behaviors are warranted.

From Seeing to Doing: Bridging Reasoning and Decision for Robotic Manipulation

arXiv:2505.08548v3 Announce Type: replace-cross Abstract: Achieving generalization in robotic manipulation remains a critical challenge, particularly for unseen scenarios and novel tasks. Current Vision-Language-Action (VLA) models, while building on top of general Vision-Language Models (VLMs), still fall short of achieving robust zero-shot performance due to the scarcity and heterogeneity prevalent in embodied datasets. To address these limitations, we propose FSD (From Seeing to Doing), a novel vision-language model that generates intermediate representations through spatial relationship reasoning, providing fine-grained guidance for robotic manipulation. Our approach combines a hierarchical data pipeline for training with a self-consistency mechanism that aligns spatial coordinates with visual signals. Through extensive experiments, we comprehensively validated FSD's capabilities in both "seeing" and "doing," achieving outstanding performance across 8 benchmarks for general spatial reasoning and embodied reference abilities, as well as on our proposed more challenging benchmark VABench. We also verified zero-shot capabilities in robot manipulation, demonstrating significant performance improvements over baseline methods in both SimplerEnv and real robot settings. Experimental results show that FSD achieves 40.6% success rate in SimplerEnv and 72% success rate across 8 real-world tasks, outperforming the strongest baseline by 30%.

Unmasking FCGR2B as a high-grade serous ovarian cancer specific marker of immune suppression and tumor progression through multi-omics mining

Transl Oncol. 2026 Apr 3;67:102748. doi: 10.1016/j.tranon.2026.102748. Online ahead of print.

ABSTRACT

BACKGROUND: Epithelial ovarian cancer (EOC) encompasses five major histological subtypes with marked genetic, immunological, and clinical heterogeneity. While genome-wide association studies (GWAS) have identified subtype-specific risk loci, a critical gap remains in understanding how plasma proteins influence immune-cell traits and contribute to EOC pathogenesis.

METHODS: We integrated subtype-stratified GWAS data from two EOC cohorts with plasma proteomics and immune-cell traits to construct protein-immune-EOC regulatory landscapes using a three-stage Mendelian randomization framework. Single-cell RNA-seq and multiplex immunofluorescence were employed to delineate the cellular distribution and spatial context of causal proteins. Subsequent analyses characterized immune infiltration, macrophage polarization, and clinicopathological associations. Drug-gene correlations were used to identify potential therapeutic targets, and transcriptomic analyses were applied to delineate the underlying transcriptional landscape.

RESULTS: We identified 20 subtype-specific protein-immune-EOC regulatory axes, with FCGR2B emerging as a causal plasma protein in immune regulation and high-grade serous ovarian cancer (HGSOC) progression. FCGR2B was highly expressed in tumor-associated macrophages and was associated with an M2-like polarization phenotype. Functional characterization revealed that FCGR2B was associated with shorter progression-free survival and an immunosuppressive tumor microenvironment. Transcriptomic analyses revealed altered NF-κB signaling upon FCGR2B knockdown, and drug-response data suggested a potential association between high FCGR2B expression and sensitivity to NF-κB inhibitors.

CONCLUSIONS: These findings delineate subtype-specific genetically informed protein-immune regulatory landscapes in EOC and identify FCGR2B as a key immunoregulatory and prognostic biomarker in HGSOC, suggesting FCGR2B as a potential therapeutic vulnerability that warrants further investigation.

PMID:41934917 | DOI:10.1016/j.tranon.2026.102748

Metabolite-gated vascular contractility switch: OXGR1 activation mechanism enables agonist therapy for rosacea erythema

Xiao et al. identify α-KG as a rosacea-associated metabolite that activates the OXGR1-Gq-MYL9 axis in the vascular smooth muscle cells to boost contractility and suppress pathological vasodilation underlying erythema. Cryo-EM reveals a bipartite-acid pocket of OXGR1 that enables structure-guided development of A-1, a selective agonist that alleviates erythema in rosacea-like models.

GISTBench: Evaluating LLM User Understanding via Evidence-Based Interest Verification

arXiv:2603.29112v1 Announce Type: new Abstract: We introduce GISTBench, a benchmark for evaluating Large Language Models' (LLMs) ability to understand users from their interaction histories in recommendation systems. Unlike traditional RecSys benchmarks that focus on item prediction accuracy, our benchmark evaluates how well LLMs can extract and verify user interests from engagement data. We propose two novel metric families: Interest Groundedness (IG), decomposed into precision and recall components to separately penalize hallucinated interest categories and reward coverage, and Interest Specificity (IS), which assesses the distinctiveness of verified LLM-predicted user profiles. We release a synthetic dataset constructed on real user interactions on a global short-form video platform. Our dataset contains both implicit and explicit engagement signals and rich textual descriptions. We validate our dataset fidelity against user surveys, and evaluate eight open-weight LLMs spanning 7B to 120B parameters. Our findings reveal performance bottlenecks in current LLMs, particularly their limited ability to accurately count and attribute engagement signals across heterogeneous interaction types.
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