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01.
arXiv (CS.CL) 2026-06-15

Does the Judge Prefer English? Evaluating Language-Switching Invariance in LLM-as-a-Judge

Authors:

Large language models (LLMs) are now widely used as automatic judges for open-ended instruction-following evaluation. This practice is convenient, scalable, and often more semantically aware than reference-based metrics, but it also introduces a new reliability question: does a judge evaluate the quality of an answer, or does it also react to the language in which the comparison is presented? We propose Judge-LS, a lightweight meta-evaluation protocol that transforms LLMBar response-pair items into English, Chinese, and Chinese-English language-switched variants. A reliable judge should preserve its preference under label-preserving language transformations and should not prefer a language when two answers are translation-equivalent. We evaluate four API-accessible judges on the full 419-item LLMBar benchmark, producing 13,408 successful pairwise judgments. Across models, Chinese and language-switched presentations induce 10.7–14.4% preference flips relative to English, and all judges achieve their highest accuracy in English. However, translation-equivalent tie probes do not reveal a systematic English preference: most probes are judged as ties, and non-tie decisions more often favor Chinese. We add confidence intervals, paired significance tests, and an automatic transformation audit with a sensitivity analysis that excludes mechanically flagged high-risk variants. The experiment requires no model training, uses only API calls, and is feasible on modest local hardware.

02.
arXiv (CS.CL) 2026-06-11

Augmenting Molecular Language Models with Local $n$-gram Memory

Transformer-based language models for SMILES strings suffer from a locality gap: standard character-level tokenization fragments chemically meaningful motifs, forcing models to repeatedly learn local syntax at the expense of long-range dependencies. To address this without disrupting standard tokenizers, we propose MolGram, which integrates a conditional $n$-gram memory module into molecular language models. MolGram maps local string patterns to learned embeddings via scalable hash lookups and dynamically injects this regional context into hidden states. Evaluations across three tasks, including unconditional molecule generation, forward reaction prediction, and single-step retrosynthesis, show that MolGram consistently improves performance. Crucially, our analyses demonstrate that MolGram outperforms baselines with 3$\times$ more parameters, establishing explicit local pattern memory as a highly efficient inductive bias.

03.
arXiv (CS.LG) 2026-06-18

Dimension-Free Convergence of Discrete Diffusion Models: Adjoint Equations Induce the Right Space

arXiv:2605.17232v2 Announce Type: replace Abstract: Discrete diffusion has become a leading framework for generative modeling in various applications including language, vision, and biology. Existing convergence theory, however, exhibits fundamental limitations. KL-based analyses diverge under singular priors such as the masked distribution, while bounds in total variation (TV) depend on the state space size $S$ and become vacuous for modern language tasks, where vocabularies contain hundreds of thousands of tokens. We develop a unified adjoint-equation-based framework that establishes dimension-free convergence guarantees in any integral probability metric (IPM). To the best of our knowledge, our bounds are the first to be entirely free of $S$ and applicable to both masked and uniform priors. Importantly, our theory relies only on a single standard rate-matrix regularity assumption and applies to general priors. Five novel techniques drive our improvements: working in the space of observables via adjoint equations rather than directly with probability measures, a regularity analysis that yields bounds on any IPM, a coupling argument that removes $S$-dependence under uniform transitions, and score-marginal cancellation and exit-routing techniques that remove $S$-dependence under masked transitions. Our framework thus sharply departs from prior analyses and avoids the shortcomings of pathspace-KL and existing TV-based approaches. Beyond convergence bounds, our framework provides a versatile toolkit for further theoretical study of discrete diffusion models, including principled choices of loss functions and dimension-free step complexity.

04.
arXiv (quant-ph) 2026-06-12

Trading symmetry for Hilbert-space dimension in Bell-inequality violation

arXiv:2601.02893v3 Announce Type: replace Abstract: In quantum information, asymmetry, i.e., the lack of symmetry, is a resource allowing one to accomplish certain tasks that are otherwise impossible. Similarly, in a Bell test using any given Bell inequality, the maximum violation achievable using quantum strategies respecting or disregarding a certain symmetry can be different. In this work, we focus on the symmetry involved in the exchange of parties and explore when we have to trade this symmetry for a lower-dimensional quantum strategy in achieving the maximal violation of given Bell inequalities. For the family of symmetric Collins-Gisin-Linden-Massar-Popescu inequalities, we provide evidence showing that there is no such trade-off. However, for several other Bell inequalities with a small number of dichotomic measurement settings, we show that symmetric quantum strategies in the minimal Hilbert space dimension can only lead to a suboptimal Bell violation. In other words, there exist symmetric Bell inequalities that can only be maximally violated by asymmetric quantum strategies of minimal dimension. In contrast, one can also find examples of asymmetric Bell inequalities that are maximally violated by symmetric correlations. The implications of these findings on the geometry of the set of quantum correlations and the possibility of performing self-testing therefrom are briefly discussed.

05.
arXiv (CS.AI) 2026-06-15

Closing the Reflection Gap: A Free Calibration Bonus for Agentic RL

Authors:

arXiv:2606.14211v1 Announce Type: new Abstract: LLMs are increasingly deployed as agents that interact with external environments and observe feedback such as execution results, error messages, and tool outputs. A well-functioning agent should be able to leverage this feedback to accurately assess its own performance. Yet we find a persistent reflection gap: LLM agents tend to mis-assess their own outputs after observing concrete environment feedback – even for questions they correctly answered – and standard RL barely helps due to a credit-assignment mismatch. To close this gap, we propose RefGRPO, a simple yet effective fix that augments standard RL algorithms with two key ingredients: a free calibration bonus computed by contrasting the agent's own reflection with the actual outcome (requiring no additional reward model, LLM judge, or external annotation), and a dynamic schedule on its coefficient. Compared to standard RL baselines, our method simultaneously improves reflection calibration (e.g., reduces underconfidence rate $44.4\% \to 7.7\%$) and task accuracy (e.g., $75.1\% \to 76.5\%$) on text-to-SQL across five benchmarks. The resulting calibrated reflection turns the agent into its own verifier grounded in environment feedback, which further enables (i) better self-improvement that uses reflections as pseudo-rewards without outcome supervision, and (ii) more effective test-time selective prediction by committing only to rollouts flagged as correct.

06.
arXiv (CS.AI) 2026-06-19

Zero-Inflated Gaussian Distributions Enable Parameter-Space Sparsity in Estimation-of-Distribution Algorithms

arXiv:2606.19369v1 Announce Type: cross Abstract: Estimation-of-distribution algorithms (EDAs) are a powerful class of evolutionary methods for black-box optimization, especially when little is known about the structure of the objective. Whereas classical evolutionary algorithms rely on hand-designed mutation and crossover operators, hard to devise for unknown problem structures, and a source of bias, EDAs sidestep operator design entirely: they fit a probability distribution to the best individuals and sample the next generation from it. EDAs are well established on continuous parameter spaces, but they have not previously been generalized to sparse ones, in which most coefficients of a good solution are exactly zero. Existing sparse black-box optimizers therefore reintroduce exactly what EDAs were designed to avoid: hand-crafted sparsity operators, bi-level schemes alternating between support set and active values, zeroing thresholds, and other baked-in assumptions. We close this gap by proposing multivariate zero-inflated Gaussian (ZIG) distributions as EDA sampling laws. A latent Gaussian model with separate indicator and value dimensions represents sparsity patterns, correlations among active parameters, and the interactions between the two, so sparsity patterns and active values are optimized jointly, hierarchy-free. We show that the latent parameters of this model are identifiable from observed samples, unlike in the missing-data settings where related constructions originate, and introduce practical amortized inversion-based estimators for them. The estimators accurately recover latent correlation structures, and on the Lunar Lander benchmark the resulting ZIG-EDA converges faster and reaches higher final returns than a dense Gaussian EDA, a hand-crafted sparse evolutionary algorithm, and an ad-hoc sparse EDA, while finding controllers with only a small fraction of parameters active.

07.
medRxiv (Medicine) 2026-06-12

Conversational Artificial Intelligence-Enabled Precision Oncology Reveals Context-Specific TGFβ and JAK/STAT Alterations in Pancreatic Cancer

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive molecular complexity, profound stromal remodeling, and limited responsiveness to systemic therapies. Although gemcitabine-based regimens remain widely utilized, the molecular pathways that influence treatment-associated biological variation are incompletely understood. The TGF{beta} and JAK/STAT signaling networks are recognized regulators of tumor progression, immune modulation, and therapeutic resistance; however, their genomic architecture in clinically stratified PDAC populations remains poorly defined. Methods: We employed a conversational artificial intelligence-driven analytical framework to investigate TGF{beta} and JAK/STAT pathway alterations in a cohort of 184 PDAC patients. Clinical and molecular data were integrated to generate age- and treatment-stratified cohorts, enabling pathway-level and gene-level analyses according to gemcitabine exposure. Findings generated through AI-assisted interrogation were subsequently evaluated using conventional statistical approaches. Results: TGF{beta} pathway alterations were identified in approximately one-quarter to one-third of tumors across clinical subgroups and demonstrated relatively stable frequencies regardless of age at diagnosis or gemcitabine treatment status. Gene-level analyses revealed that pathway disruption was predominantly driven by recurrent alterations in SMAD4, with additional low-frequency events involving TGFBR1 and TGFBR2. Notably, TGFBR2 mutations were significantly more frequent among late-onset PDAC patients receiving gemcitabine compared with untreated late-onset patients (8.8% vs. 1.4%; p = 0.04), suggesting a potential treatment-associated enrichment. In contrast, JAK/STAT pathway alterations were rare throughout the cohort, with only isolated mutations observed in pathway components including JAK1, JAK2, JAK3, STAT1, STAT3, and related regulatory genes. No significant differences in JAK/STAT alteration frequencies were identified according to age or treatment exposure. Conclusions: TGF{beta} and JAK/STAT pathways exhibit distinct genomic architectures in PDAC. TGF{beta} pathway disruption represents a recurrent feature of disease biology, largely driven by SMAD4 alterations, while TGFBR2 enrichment in gemcitabine-treated late-onset tumors suggests a potential context-specific association worthy of further investigation. Conversely, genomic alterations within the JAK/STAT pathway are uncommon, indicating that pathway activity may be regulated predominantly through non-genomic mechanisms. These findings demonstrate the utility of conversational artificial intelligence agents for rapid, scalable, and clinically contextualized pathway interrogation and support future studies integrating multi-omic data to refine precision medicine strategies in PDAC.

08.
arXiv (CS.LG) 2026-06-17

Learning Upper Lower Value Envelopes to Shape Online RL: A Principled Approach

arXiv:2510.19528v2 Announce Type: replace-cross Abstract: We investigate the fundamental problem of leveraging offline data to accelerate online reinforcement learning - a direction with strong potential but limited theoretical grounding. Our study centers on how to learn and apply value envelopes within this context. To this end, we introduce a principled two-stage framework: the first stage uses offline data to derive upper and lower bounds on value functions, while the second incorporates these learned bounds into online algorithms. Our method extends prior work by decoupling the upper and lower bounds, enabling more flexible and tighter approximations. In contrast to approaches that rely on fixed shaping functions, our envelopes are data-driven and explicitly modeled as random variables, with a filtration argument ensuring independence across phases. The analysis establishes high-probability regret bounds determined by two interpretable quantities, thereby providing a formal bridge between offline pre-training and online fine-tuning. Empirical results on tabular MDPs demonstrate substantial regret reductions compared with both UCBVI and prior methods while remaining competitive with related approaches.

09.
arXiv (quant-ph) 2026-06-16

Information Is Not Physical: Possibility Spaces, Erasure, and the Structure of Unrealized Alternatives

arXiv:2606.15120v1 Announce Type: cross Abstract: The slogan ``information is physical,'' introduced by Rolf Landauer and developed through quantum information theory and black-hole thermodynamics, has achieved near-axiomatic status in modern physics. Yet the ontological status of information remains surprisingly underexamined: most discussions either reduce information to a form of energy or treat it as a purely mathematical object. This paper proposes a third position. I argue that information is neither a physical substance nor a free-floating abstraction, but rather the structure of physically realizable alternatives – a counterfactual structure that a physical system instantiates in virtue of the possibility space available to it. Building on Shannon's combinatorial definition, the Landauer principle, the no-cloning theorem, and the black-hole information paradox, I show that the informational content of any physical event is constituted by the set of outcomes that could have occurred but did not. This counterfactual reading dissolves several persistent confusions: it explains why erasing information dissipates heat without making information ``material,'' why quantum superposition is informationally richer than any classical mixture, and why information loss in black holes is physically significant beyond mere bookkeeping. The proposal sits within a structural-realist framework but departs from standard structural realism by locating the relevant structure in modal, not merely actual, relations. I conclude by sketching implications for the foundations of quantum mechanics, quantum gravity, and scientific ontology more broadly.

10.
arXiv (CS.CV) 2026-06-17

SceneCompleter: Dense 3D Scene Completion for Generative Novel View Synthesis

Generative models have shown great promise for novel view synthesis (NVS) by leveraging strong image generation priors. However, existing approaches typically follow a 2D inpainting paradigm, first completing missing image regions and then performing 3D reconstruction. This strategy often causes geometry distortion and appearance drift, as 2D inpainting models cannot reliably infer the underlying 3D structure required for cross-view consistent generation. In this paper, we propose SceneCompleter, a geometry-aware framework that reformulates generative NVS as dense 3D scene completion. Instead of hallucinating isolated 2D views, SceneCompleter jointly completes geometry and appearance through a geometry-appearance dual-stream diffusion model in a spatially aligned RGBD latent space. To provide holistic scene context, we further introduce a Scene Embedder that conditions generation on global semantic and stylistic information from reference images. The completed RGBD predictions are then aligned and integrated into an expandable 3D scene representation, enabling iterative and coherent scene completion. Extensive experiments on in-domain and out-of-distribution datasets demonstrate that SceneCompleter produces visually plausible and geometrically consistent novel views across diverse scenarios. Project Page: https://chen-wl20.github.io/SceneCompleter

11.
arXiv (CS.LG) 2026-06-15

A Longitudinal Attribute-Conditioned Neural Network for Modeling Health-State Transition Probabilities in Temporally Irregular Data: The LANTERN Framework

arXiv:2606.13880v1 Announce Type: new Abstract: Accurate estimation of long-term care transition probabilities is central to disability insurance pricing, reserving, and solvency assessment. Classical actuarial multi-state models commonly rely on Markov, semi-Markov, or proportional-hazard specifications, which provide a direct connection to cohort projection but may be restrictive for irregular longitudinal health data with nonlinear aging patterns and heterogeneous covariate histories. This paper develops a well-calibrated estimator of multi-state transition probabilities for irregular longitudinal health data. The model learns from individual health history, incorporates the time elapsed between observations, and conditions transition probabilities on demographic and socioeconomic attributes. It produces a valid probability distribution over the next observed health state, with four possible states: healthy, mild disability, severe disability, and death. Individual probabilities are aggregated by age group and origin state to form transition matrices compatible with actuarial cohort projection. Using longitudinal data from the Health and Retirement Study, we compare the proposed estimator with logistic regression, gradient-boosted trees, a recurrent neural network, and a last-state persistence benchmark. The evaluation considers probabilistic accuracy, endpoint discrimination and calibration for severe disability and death, risk concentration, and transition matrix error after aggregation. The proposed estimator improves severe disability discrimination relative to logistic regression and gradient-boosted tree benchmarks, maintains strong calibration, and yields the lowest transition matrix error among the evaluated models in the held-out test analysis. Results show that a structured machine learning estimator can support long-term care transition modeling when judged by calibration and projection fidelity, beyond discrimination.

12.
arXiv (CS.LG) 2026-06-19

Efficient Neural Network Model Selection for Few-Class Application Datasets

arXiv:2606.19712v1 Announce Type: new Abstract: While much effort has focused on developing and benchmarking high-performance neural networks, less attention has been given to how dataset properties, known to practitioners, can guide efficient model selection. Neural models are typically evaluated on datasets with thousands of classes, yet many real-world applications involve fewer than ten. To address this understudied but common setting, we develop a measure of classification difficulty based on data-side properties and show how it enables more efficient model selection for few-class datasets, where traditional approaches are less effective. We term this phenomenon "few-class distinctiveness". Our metric allows comparison of models and datasets 6 to 29$\times$ faster than repeated training and testing. Leveraging this insight, we extend scaled model families below the smallest published models, achieving greater efficiency at similar accuracy, for example models up to 42% smaller than YOLOv5-nano for a mobile robot task. Targeting resource-constrained applications, we demonstrate few-class model selection across mobile robot, drone, and IoT scenarios, highlighting practical gains in efficiency without sacrificing performance.

13.
arXiv (quant-ph) 2026-06-17

Intrinsic Pointer Basis and Irreversible Classicality from Coherence Contraction

Authors:

arXiv:2604.23304v4 Announce Type: replace Abstract: This work analyzes an operational route to classical behavior for reduced quantum states using the intrinsic reference basis (IRB). Relative to a fixed physical conjugation, the IRB separates intrinsic populations from a real antisymmetric cohesion sector. A globally bounded cohesion index is defined and its exponential contraction is proved for phase-free dephasing dynamics aligned with the IRB; for general aligned dephasing, the corresponding modulus-based coherence functional contracts at the same computable rates. The results provide distance bounds to the IRB-diagonal description and a logarithmic upper bound on the time required to reach a prescribed experimental tolerance. The IRB projectors constitute state-derived candidate pointer sectors, and they become dynamically stable pointer sectors when the effective dephasing generator is aligned with them and damps the relevant inter-sector coherences. Degenerate population sectors lead naturally to block-classicality and protected intra-block coherence. In a two-level active sector, the cohesion index equals fringe visibility, giving a direct interferometric test of the contraction law. The construction is independent of any spacetime- or unification-emergence hypothesis and is intended as a channel-level complement to environment-induced einselection.

14.
arXiv (CS.LG) 2026-06-17

Noise-Driven Exploration and Transient Freezing Select Flat Minima in Stochastic Gradient Descent

arXiv:2601.10962v2 Announce Type: replace Abstract: Stochastic gradient descent (SGD) is central to deep learning, yet the dynamical origin of its preference for flatter, more generalizable solutions remains unclear. Here, by analyzing SGD learning dynamics, we identify a nonequilibrium mechanism that governs solution selection during training. Numerical experiments reveal a transient exploratory phase in which SGD trajectories repeatedly escape sharp valleys and migrate toward flatter regions of the loss landscape before becoming confined to a final basin. Using a tractable physical model, we show that SGD noise reshapes the loss landscape into an effective potential that preferentially stabilizes flat solutions. We further uncover a transient freezing mechanism: as training progresses, the flattening landscape suppresses transitions between competing valleys. Stronger SGD noise delays this freezing transition, prolonging the exploratory phase and thereby increasing the probability of convergence to flatter minima. Together, these results provide a unified physical framework connecting learning dynamics, loss-landscape geometry, and generalization, and suggest guiding principles for the design of more effective optimization algorithms.

15.
bioRxiv (Bioinfo) 2026-06-18

MorphoStat: A Statistics-Aware Pipeline for Morphological Profiling Analysis

Authors:

High-content imaging produces thousands of morphological measurements per cell. Interpreting these measurements requires normalization to remove plate effects, statistical tests selected on the basis of data distribution, and control over false discoveries across many features tested at once. MorphoStat is an open-source Python pipeline that applies this sequence of steps automatically. Given a CSV file from CellProfiler or a compatible imaging platform, it removes low-quality wells, normalizes each plate against DMSO controls using a MAD-scaled z-score, routes each feature to a parametric or nonparametric test based on a distributional check, applies Benjamini Hochberg correction, and writes out results and publication-ready figures. On the BBBC021 benchmark (MCF-7 breast-cancer cells, 632 wells, 473 features), MorphoStat recovered 12 of 13 known mechanism-of-action classes in principal component space, confirming that the normalization and statistical routing work as intended. The tool is available at https://github.com/Almunthir334/morphostat (DOI: 10.5281/zenodo.20354069) under the MIT license.

16.
arXiv (CS.AI) 2026-06-16

Red-Teaming Agent Execution Contexts: Open-World Security Evaluation on OpenClaw

arXiv:2605.11047v2 Announce Type: replace-cross Abstract: Agentic language-model systems increasingly rely on mutable execution contexts, including files, memory, tools, skills, and auxiliary artifacts, creating security risks beyond explicit user prompts. This paper presents DeepTrap, an automated framework for discovering contextual vulnerabilities in OpenClaw. DeepTrap formulates adversarial context manipulation as a black-box trajectory-level optimization problem that balances risk realization, benign-task preservation, and stealth. It combines risk-conditioned evaluation, multi-objective trajectory scoring, reward-guided beam search, and reflection-based deep probing to identify high-value compromised contexts. We construct a 42-case benchmark spanning six vulnerability classes and seven operational scenarios, and evaluate nine target models using attack and utility grading scores. Results show that contextual compromise can induce substantial unsafe behavior while preserving user-facing task completion, demonstrating that final-response evaluation is insufficient. The findings highlight the need for execution-centric security evaluation of agentic AI systems. Our code is released at: https://github.com/ZJUICSR/DeepTrap

17.
arXiv (math.PR) 2026-06-12

Counterintuitive problems in discrete probability

arXiv:2606.07516v2 Announce Type: replace Abstract: This manuscript contains a collection of counterintuitive problems in discrete probability, together with detailed solutions. The dataset was constructed as part of a broader research project investigating the capabilities of the latest-generation Large Language Models (LLMs) in solving discrete probability problems, in order to assess whether LLMs tend to make systematic reasoning errors associated with known cognitive biases. The problems collected here are specifically designed to challenge heuristic reasoning strategies that often lead to intuitively appealing but mathematically incorrect conclusions. The dataset combines several types of problems. Some are adapted from classical probabilistic paradoxes and cognitive-bias literature, while others originate from recreational mathematics sources or were developed by ourselves following similar principles. The primary purpose of this document is to provide a transparent and publicly accessible reference for the problems used in our experimental evaluation of language models, as well as providing detailed human-made solutions. At the same time, we believe that this collection may also prove useful for future research on probabilistic reasoning, cognitive biases, and the evaluation of reasoning capabilities in artificial intelligence systems.

18.
medRxiv (Medicine) 2026-06-16

Infections and suicide and self-harm: a population-based matched cohort study

Background Infections have been associated with adverse mental health outcomes, including suicide, but evidence beyond severe or central nervous system infections is limited. We investigated associations between a range of acute infections and subsequent suicide/self-harm outcomes. Methods We conducted six infection-specific matched cohort studies using English primary care records from the Clinical Practice Research Datalink Aurum (2007-2024), linked to hospital admissions and mortality data. Adults ([≥]18 years) with a primary care record of infection (gastroenteritis, lower respiratory tract [LRTI], skin/soft-tissue [SSTI], urinary tract [UTI], sepsis, meningitis/encephalitis [positive control]) were matched (age, sex, practice, calendar period) to up to five comparators without infection. We estimated hazard ratios (HRs) for suicide/self-harm outcomes using Cox regression, stratified by matched set and implicitly adjusting for matching factors, with additional adjustment for deprivation, lifestyle factors, and comorbidities. We examined whether associations varied over time, by infection severity, antimicrobial treatment, sex, and prior mental health conditions. Findings Cohorts ranged from 18,192 individuals with meningitis/encephalitis (matched to 90,915 without) to 398,099 with SSTI (matched to 1,743,747). After adjustment, individuals with infection had a higher hazard of suicide/self-harm outcomes than comparators across all cohorts: sepsis (HR 1.79, 95% CI 1.65-1.93), gastroenteritis (1.62, 1.55-1.70), meningitis/encephalitis (1.56, 1.32-1.84), UTI (1.41, 1.33-1.50), SSTI (1.37, 1.31-1.43), and LRTI (1.37, 1.31-1.44). Risk was highest in the year post-infection, attenuating over time, and was higher among severe infections and those without prior mental health conditions. Interpretation Common acute infections recorded in primary care are associated with increased risk of suicide and self-harm, particularly following severe infections and in the year post-infection. Findings support suicide risk monitoring following acute infection, particularly among individuals without prior mental health conditions, and highlight infection prevention as a potentially modifiable strategy in vulnerable populations. Funding Wellcome and La Caixa. Copyright This work is licensed under a Creative Commons Attribution (CC BY) licence.

19.
PLOS Medicine 2026-05-15

Spatial transcriptomic-metabolic features of tumor foci and tumor capsule in microvascular invasion with hepatocellular carcinoma: A spatial multi-omics study

Authors:

by Zhi-Hui Luo, Na Wang, Jingwei Zhao, Fei Long, Si Wu, Wei Zhong, Wei-Ming Chen, Bicheng Wang, Kun Wang, Yufeng Yuan, Jingjiao Zhou, Chunhui Yuan, Fubing Wang Background Microvascular invasion (MVI) is closely related to the recurrence and metastasis of hepatocellular carcinoma (HCC), but the underlying cellular mechanism remains largely elusive. This study aims to elucidate the regional cellular discrepancy between MVI-positive (MVI+) and MVI-negative (MVI−) HCC by integrating Spatial transcriptomics (ST) and spatial metabolomics (SM). Methods and findings ST and SM were performed on six tissue samples from four patients (including 2 MVI+, 2 MVI−, and 2 paratumor tissues), with the integration of 79 public single-cell RNA sequencing datasets of HCC. Patient identity was used as a covariate in the linear equation for regional differentially expressed gene analysis with the ST data. Clinical validation was conducted through multiplex immunofluorescence staining in 79 patients, together with external validation in the cancer genome atlas (TCGA)-liver hepatocellular carcinoma (LIHC) cohort (n = 299) and an independent microarray dataset (n = 62). For cell-type-specific metabolic profiling, spatial transcriptomic-metabolic registration was performed. The functional roles of key metabolites were further validated in vitro using inflammatory cancer-associated fibroblasts (iCAFs) derived from hepatic stellate cells (HSCs) and primary CAFs through co-culture models and various functional assays assessing cell proliferation, migration, and invasion. In the tumor lesion, a malignant STMN1+HMGN2+GPC3+ cell subtype enriched in MVI+ HCC was identified, which exhibited enhanced proliferative activity and was associated with poor prognosis. This finding was further confirmed in a local cohort of 79 patients, where multiplex immunofluorescence staining for the three genes (STMN1, HMGN2, and GPC3) showed significantly higher expression in the MVI+ group than in the MVI− group (p = 0.046). Integrated SM analysis further revealed that this cell population underwent metabolic reprogramming characterized by suppressed glycerolipid metabolism. In the tumor capsule, iCAFs-related genes were downregulated in MVI+ cases, and iCAFs were located distally from the tumor boundary. Spatial metabolite mapping showed a strong correlation between taurine and iCAFs, and functional assays demonstrated that taurine promotes HCC proliferation and migration by suppressing iCAF activity. One limitation of this study is the small sample size of spatial omics data, which hinders a more complete molecular functional analysis of the STMN1+HMGN2+GPC3+ cell subtype and iCAFs in MVI+ HCC. Larger-scale ST cohorts are required to further validate and expand the findings of this study. Conclusions This integrative spatial atlas proposes a hypothesis that there exists a highly proliferative and metabolically reprogrammed malignant cell subtype in the tumor lesion of MVI+ HCC, and that taurine in the tumor capsule modulates iCAF activity to influence tumor progression. The exploratory results provide mechanistic insights into MVI-related HCC progression and offer potential avenues for targeted therapeutic intervention of MVI+ HCC.

20.
PLOS Computational Biology 2026-06-22

Beyond the canonical: The role of post-transcriptional regulation in drug-target interaction prediction

by Md Istiaq Ansari, Khandakar Tanvir Ahmed, Debby D. Wang, Kirill Medvedev, Wei Zhang Protein isoforms produced from the same gene through post-transcriptional regulatory mechanisms, such as alternative splicing, can substantially alter protein structure and function, including drug-binding properties. However, most existing drug-target interaction (DTI) and drug-target affinity (DTA) prediction models rely exclusively on a single representative protein sequence per gene, typically the canonical or longest isoform, thereby overlooking the functional diversity introduced by alternative isoforms. This assumption can introduce bias, limit generalizability, and compromise the biological validity of model predictions. In this study, we systematically investigate the impact of protein isoform variation on DTI prediction accuracy. Our results show that substituting the canonical sequence with an alternative isoform often leads to substantial declines in predictive performance. Structural and binding affinity analyses further reveal that these discrepancies are frequently associated with changes in predicted binding-site configurations, which we further examine through controlled perturbations of binding-site residues. These experiments suggest that even subtle alterations in binding regions can lead to inconsistent DTI predictions. Overall, our findings uncover a critical limitation in current DTI modeling frameworks and underscore the importance of incorporating isoform-specific information to better reflect biological reality and improve therapeutic relevance. The codes and datasets are available at https://github.com/compbiolabucf/DTIVariant.

21.
arXiv (CS.CV) 2026-06-15

Representation Forcing for Bottleneck-Free Unified Multimodal Models

Unified multimodal models (UMMs) aim to handle perception and generation in a single model. Yet existing UMMs still rely on a frozen, separately pretrained VAE for image generation, imposing a structural bottleneck. Naively removing it introduces a quality gap, as the model must learn both high-level structure and low-level details from raw pixels. In this paper, we propose Representation Forcing (RF), a technique that closes this gap by making representation prediction a native capability of the model. Concretely, RF forces the decoder to autoregressively predict visual representations as intermediate tokens before pixels; these tokens then stay in context to guide pixel diffusion within the same backbone. By turning representations from perception outputs into generation targets, RF eliminates the need for any external generative latent space. We find that RF benefits both understanding and generation. On image generation, our pixel-space model with RF matches state-of-the-art VAE-based unified models. On image understanding, pixel-space RF generally outperforms its VAE-based variant. Together, these results offer an effective step toward end-to-end, bottleneck-free UMMs.

22.
arXiv (CS.AI) 2026-06-18

The Long Delay to Arithmetic Generalization: When Learned Representations Outrun Behavior

arXiv:2604.13082v2 Announce Type: replace-cross Abstract: Grokking in transformers trained on algorithmic tasks is characterized by a long delay between training-set fit and abrupt generalization, but the source of that delay remains poorly understood. In encoder-decoder arithmetic models, we argue that this delay reflects limited access to already learned structure rather than failure to acquire that structure in the first place. We study one-step Collatz prediction and find that the encoder organizes parity and residue structure within the first few thousand training steps, while output accuracy remains near chance for tens of thousands more. Causal interventions support the decoder bottleneck hypothesis. Transplanting a trained encoder into a fresh model accelerates grokking by 2.75 times, while transplanting a trained decoder actively hurts. Freezing a converged encoder and retraining only the decoder eliminates the plateau entirely and yields 97.6% accuracy, compared to 86.1% for joint training. What makes the decoder's job harder or easier depends on numeral representation. Across 15 bases, those whose factorization aligns with the Collatz map's arithmetic (e.g., base 24) reach 99.8% accuracy, while binary fails completely because its representations collapse and never recover. The choice of base acts as an inductive bias that controls how much local digit structure the decoder can exploit, producing large differences in learnability from the same underlying task.

23.
arXiv (CS.AI) 2026-06-11

Bimanual Robot Manipulation via Multi-Agent In-Context Learning

arXiv:2604.20348v2 Announce Type: replace-cross Abstract: Language Models (LLMs) have emerged as powerful reasoning engines for embodied control. In particular, In-Context Learning (ICL) enables off-the-shelf, text-only LLMs to predict robot actions without any task-specific training while preserving their generalization capabilities. Applying ICL to bimanual manipulation remains challenging as the high-dimensional joint action space and tight inter-arm coordination constraints rapidly overwhelm standard context windows. To address this, we introduce BiCICLe (Bimanual Coordinated In-Context Learning), the first framework that enables standard LLMs to perform few-shot bimanual manipulation without fine-tuning. BiCICLe frames bimanual control as a multi-agent leader-follower problem, decoupling the action space into sequential, conditioned single-arm predictions. Evaluated on 13 tasks from the TWIN benchmark, BiCICLe achieves 70.5% average success rate, outperforming the best training-free baseline by 6.1 percentage points and surpassing most supervised methods. We also demonstrate superior real-world performance on 3 tasks without hardware-specific retraining.

24.
arXiv (CS.CV) 2026-06-16

Human Cognition in Machines: A Unified Perspective of World Models

This report of world models distinguishes prior works by the cognitive functions they innovate. Many works claim an almost human-like cognitive capability in their world models. To evaluate these claims requires a proper grounding in first principles from human and machine cognition theory. In moving towards human-like world models we present a conceptual unified framework for world models that fully incorporates all the cognitive functions (i.e., memory, perception, language, reasoning, imagining, motivation, and metacognition) and identify gaps in existing research as a guide for future states of the art. In particular, we find that motivation (especially intrinsic motivation) and metacognition remain drastically under-researched, and we propose concrete directions to address these gaps informed by active inference and global workspace theory. We also introduce epistemic world models, a new category encompassing agent frameworks for scientific discovery that operate over structured knowledge. Our taxonomy, applied to video, embodied, and epistemic world models, suggests research directions where prior taxonomies have not.

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arXiv (CS.AI) 2026-06-11

ATLAS: Active Theory Learning for Automated Science

arXiv:2606.12386v1 Announce Type: cross Abstract: Advancing scientific understanding through mechanistic modeling requires posing the right experimental questions to yield maximally informative data. To automate this pursuit within cognitive science, we introduce ATLAS (Active Theory Learning for Automated Science), an active learning framework for the data-driven discovery of interpretable behavioral models. ATLAS iterates between generating mechanistic hypotheses–instantiated as a diverse ensemble of sparse neural networks (Disentangled RNNs)–and designing experiments that optimally distinguish between them. We test this approach on the problem of recovering reinforcement learning agents from their behavior in bandit tasks. ATLAS designs varied sequences of qualitatively novel experiments with temporal structure tailored to underlying agent characteristics. The models trained on these experiments are evaluated against a comprehensive set of metrics for mechanistic modeling that capture behavioral, structural, and computational similarity. ATLAS achieves a 5-10x improvement in sample efficiency across all metrics compared to random experimentation, and its performance is further validated against expert-designed experiments derived from literature. These in silico results showcase ATLAS's potential to accelerate human-interpretable insights in cognitive science and other domains where scientific inquiry relies on discovering mechanistic models.