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01.
Nature (Science) 2026-06-09

How ice forms is a mystery — now scientists are cracking the case

Authors:

Theories about how ice crystals grow in cooling liquids are wildly inaccurate when compared with experimental data, but studies are starting to illuminate the earliest moments in freezing. Theories about how ice crystals grow in cooling liquids are wildly inaccurate when compared with experimental data, but studies are starting to illuminate the earliest moments in freezing.

02.
arXiv (CS.CL) 2026-06-18

Possible or Definite? A Benchmark for Evaluating Diagnostic Uncertainty Preservation in Clinical Text

Large language models (LLMs) are increasingly used for clinical text tasks such as summarization and revision. While most studies evaluate the fluency and coherence of LLM-generated text, whether LLMs correctly preserve diagnostic uncertainty remains underexplored. In clinical practice, phrases such as ``possible pneumonia'' communicate the strength of available evidence and directly guide decisions about follow-up testing and treatment. Altering these uncertainty expressions can change the clinical meaning entirely. In this paper, we systematically evaluated this problem in two steps. First, we constructed a benchmark of 1,200 clinical documents with 9,184 uncertainty annotations across five levels. Second, we evaluated three LLMs on this benchmark. Our results show that (1) LLMs preserve the original uncertainty cues poorly, often less than half the time; (2) LLMs struggle with nuanced distinctions between adjacent levels. This work reveals a failure mode not captured by standard evaluation metrics and provides implications for the safe deployment of LLMs in clinical workflows.

03.
arXiv (CS.CV) 2026-06-19

Cinematic Compositing Using Character-Environment-Harmonized Video Generation Models

Cinematic compositing aims to integrate green-screen characters into novel environments while maintaining physical and photometric realism. Previous methods often fail to capture the complex bidirectional interactions between characters and their surroundings, which we characterize as Character-to-Environment (C2E) physical interaction and Environment-to-Character (E2C) lighting harmonization. To address this, we propose an end-to-end video diffusion framework that jointly models C2E and E2C interactions, specifically handling the challenges of interactive props. Our approach introduces a tri-mask-guided architecture with RGB-D joint denoising to ensure physically consistent interactions among the character, props, and environment. We further develop an efficient prior-driven data curation pipeline to construct high-quality relighting pairs without expensive rendering. Finally, a reference-conditioned mechanism enables controllable environment synthesis and precise prop replacement. Extensive experiments demonstrate that our framework significantly outperforms existing methods in cinematic-quality dynamic video compositing.

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

A Complexity Measure for Active Learning in Multi-group Mean Estimation

arXiv:2606.14690v1 Announce Type: new Abstract: We study a max-risk objective for active learning in a multi-group mean estimation $d$-armed bandits: a learner adaptively allocates a budget of $T$ samples across $d$ groups to minimize the worst-case uncertainty index $\max_{k\in[d]}\sigma_k^2/n_k$, where $\sigma_k$ is the standard deviation of the distribution of arm $d$, and $n_k$ is the number of times arm $d$ is sampled. We develop a local minimax framework and prove the first general lower bound for this objective, valid for any finite-variance hypothesis class. The bound separates difficulty into three orthogonal factors: a budget term, a heteroscedasticity index measuring how unevenly the uncertainty is spread across arms, and a model-dependent complexity measure, the Variance Local Curvature ($\mathrm{VLC}$), which captures how much information a local change of variance creates inside the hypothesis class. For smooth classes, the $\mathrm{VLC}$ is a reparametrization of a variance–Fisher information, with closed-form values for common families. Benchmarking against the strongest available upper bound shows near-optimality up to logarithmic factors in broad regimes, and pinpoints a systematic gap in highly heterogeneous instances. Our proof introduces two key ingredients: a loss-induced $\ell_1$ geometry on the decision space, and a representation-based instance generator that reduces hard-instance construction to an explicit random matrix calculation.

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

Process-Verified Reinforcement Learning for Theorem Proving via Lean

arXiv:2606.20068v1 Announce Type: new Abstract: While reinforcement learning from verifiable rewards (RLVR) typically has relied on a single binary verification signal, symbolic proof assistants in formal reasoning offer rich, fine-grained structured feedback. This gap between structured processes and unstructured rewards highlights the importance of feedback that is both dense and sound. In this work, we demonstrate that the Lean proof assistant itself can serve as a symbolic process oracle, supplying both outcome-level and fine-grained tactic-level verified feedback during training. Proof attempts are parsed into tactic sequences, and Lean's elaboration marks both locally sound steps and the earliest failing step, yielding dense, verifier-grounded credit signals rooted in type theory. We incorporate these structured rewards into a GRPO-style reinforcement learning objective with first-error propagation and first-token credit methods that balances outcome- and process-level advantages. Experiments with STP-Lean and DeepSeek-Prover-V1.5 show that tactic-level supervision outperforms outcome-only baselines in most settings, delivering improvements on benchmarks such as MiniF2F and ProofNet. Beyond empirical gains, our study highlights a broader perspective: symbolic proof assistants are not only verifiers at evaluation time, but can also act as process-level reward oracles during training. This opens a path toward reinforcement learning frameworks that combine the scalability of language models with the reliability of symbolic verification for formal reasoning.

07.
arXiv (CS.LG) 2026-06-18

TS-Fault: Benchmarking Time Series Forecasters Against Structural Faults

arXiv:2606.18539v1 Announce Type: new Abstract: Time series forecasting (TSF) underpins consequential decisions in energy, transportation, finance, and healthcare, yet TSF models are almost universally ranked by a single number (e.g., average error) on clean held-out data, under the implicit assumption that it predicts deployed reliability. However, real faults are not i.i.d noise but structured events with temporal shape, broken cross-variable dependencies, regime change coupled with missingness, and causal propagation across a sensing pipeline. Treating TSF robustness as a data-quality problem, we present TS-Fault, a benchmark that evaluates forecasting models under explicit, parameterized fault scenarios with controllable semantic difficulty. TS-Fault organizes recurring failures into four modes along two orthogonal axes (observation- vs mechanism-level; univariate vs multivariate) and injects each fault into the most prediction-critical window via a unified importance score. This design enables robustness to be tested against the structures models actually rely on, rather than reduced to generic noise sensitivity. We evaluate 21 models across 6 datasets, 4 modes, and 5 difficulty levels under a paired clean/corrupt protocol. The results reveal three findings that contradict common leaderboard intuition: (i) clean-data accuracy anti-correlates with robustness; (ii) clean rankings are preserved under observation-level faults but reshuffled under mechanism-level faults; and (iii) all catastrophic failures occur under mechanism-level faults, with foundation models achieving the highest clean-data accuracy yet exhibiting the greatest fragility. The code is publicly available at https://github.com/Ray-zyy/TS-Fault.

08.
arXiv (quant-ph) 2026-06-12

From 2D Yang-Mills to Calogero-Sutherland via a colored particle

arXiv:2606.13388v1 Announce Type: cross Abstract: We study Yang-Mills theory coupled to a particle on a cylinder, where gauge invariance and compactness reduce the dynamics to a finite dimensional quantum system. In the Abelian case, this yields a model equivalent to the Landau problem on a torus, with a degenerate ground state structure. We generalize this construction to non-Abelian gauge groups and show that, for SU(N), the system reduces to a one dimensional quantum many body problem with a singular Calogero-Sutherland-type interaction.

09.
arXiv (CS.LG) 2026-06-16

Elastic ODYN: Differentiable Optimization for Infeasible Control and Learning in Robotics

arXiv:2606.16564v1 Announce Type: cross Abstract: Robotic systems routinely encounter conflicting objectives, modeling errors, and degenerate contact conditions that render quadratic programs (QPs) infeasible. Yet most optimization solvers and differentiable QP layers assume feasibility, leading to numerical failures, unstable gradients, or solver breakdown when constraints cannot be simultaneously satisfied. We present Elastic ODYN, a primal–dual non-interior-point QP solver that handles infeasibility through smooth squared-$\ell_2$ elastic relaxations. The resulting formulation remains well posed under ill-conditioning and degeneracy, supports warm starting, and converges to closest-to-feasible solutions when no feasible point exists. A lightweight refinement stage recovers physically meaningful dual variables from the elastic solution. Building on this framework, we develop Elastic OdynLayer, a differentiable QP layer with stable gradients under infeasibility, and Elastic OdynSQP, an infeasibility-aware SQP method that resolves inconsistent subproblems and intrinsically infeasible optimal control tasks through selective constraint relaxation. We evaluate the framework on benchmark QPs, singular contact mechanics, differentiable parameter identification, and quadrupedal and humanoid trajectory optimization. Across all settings, Elastic ODYN consistently outperforms state-of-the-art elastic QP solvers in robustness, warm-start performance, and convergence reliability, enabling optimization, simulation, control, and learning beyond the feasibility assumptions of existing methods.

10.
arXiv (CS.AI) 2026-06-16

UXBench: Measuring the Actionability of LLM-Generated UX Critiques

arXiv:2606.16262v1 Announce Type: cross Abstract: Large language models (LLMs) are increasingly deployed as UX judges that inspect interfaces, diagnose usability problems, and propose repairs. Yet no controlled benchmark measures whether the resulting critiques are reliable and actionable across heterogeneous product surfaces. We introduce UXBench, a benchmark for evaluating LLMs as interaction-grounded UX judges. UXBench comprises local-first runnable web fixtures spanning ten product-surface families, paired with coverage-gated browser exploration that forces models to collect interaction evidence before reporting. Each judge model produces a structured UX report over seven rubric dimensions; report quality is measured by whether a fixed downstream repair agent can improve the interface based on the critique. We evaluate eight frontier models under both an automated repair-lift protocol and a blind human validation study. Results show that UX judging is neither saturated nor one dimensional: models differ meaningfully in report actionability, exhibit distinct rubric-level repair signatures, vary in fixture-level reliability, and trade leadership across surface categories

11.
medRxiv (Medicine) 2026-06-24

Cardiologists perspectives on sociocultural and structural factors shaping cardiovascular genetic testing

Introduction: Genetic testing is increasingly central to the diagnosis and management of cardiovascular genetic conditions. However, use and follow-through vary across patient populations. Examining clinician perspectives on sociocultural and structural factors influencing testing is important for understanding these differences and informing public health genomics research and implementation efforts. Methods: We conducted semi-structured interviews with 15 cardiologists from health systems across the United States who have integrated cardiogenetics in their practice. Interviews explored experiences diagnosing cardiovascular genetic conditions among patients from underrepresented backgrounds, as well as approaches to incorporating social and contextual information into care. Data were coded thematically and analyzed using a framework analysis guided by the Health Equity Implementation Framework and Social Determinants of Health domains. Results: Clinicians described multi-level factors shaping genetic testing practices, including patient-provider interactions, clinical workflows, health system infrastructure, and broader policy contexts. Key themes included challenges communicating complex genetic information across language and literacy differences; patient trust shaped by prior healthcare experiences; fragmented insurance coverage separating genetic testing from genetic counseling; and challenges interpreting variants of uncertain significance, particularly for populations underrepresented in genomic reference databases. Clinicians also described adaptive strategies, such as interdisciplinary collaboration, telehealth, and patient assistance programs, that supported testing in some settings but were often inconsistent or resource-dependent. Conclusion: Among cardiologists using genetic testing, system-level and sociocultural factors shape the feasibility and downstream use of cardiovascular genetic testing. Findings highlight considerations for public health-informed genomic infrastructure that accounts for social context, supports communication, and reduces reliance on individual clinician workarounds, with implications for clinical decision support and related public health genomics initiatives.

12.
arXiv (CS.LG) 2026-06-11

Intermittent time series forecasting: local vs global models

arXiv:2601.14031v2 Announce Type: replace-cross Abstract: Forecasting intermittent time series, which contain zeros, is a crucial challenge in supply chains as inventory policies require probabilistic forecasts to establish safety levels. Intermittent time series are commonly forecast using local models, trained individually on each time series. In the last years global models, trained on a large collection of time series, have become popular for time series forecasting. Global models are often based on neural networks or gradient boosted trees. We carry out the first study comparing state-of-the-art probabilistic local and global models on intermittent time series. For global models we consider three different distribution heads suitable for intermittent time series: negative binomial, hurdle-shifted negative binomial and Tweedie. To the best of our knowledge, this is the first use of the latter two with neural networks. We perform experiments on five datasets comprising overall more than 40'000 real-world time series. Among global models, TiDE, a simple neural network architecture, achieves the best accuracy; it also consistently outperforms local models and has lower computational requirements. Large global models are instead much more computationally demanding and less accurate. Among the distribution heads, the Tweedie provides the best estimates of the highest quantiles.

13.
arXiv (CS.LG) 2026-06-18

PACT: Preserving Anchored Cores in Task-vectors for Model Merging

arXiv:2606.18627v1 Announce Type: new Abstract: Model merging has emerged as a training-free alternative to multi-task learning, aiming to combine multiple task-specific fine-tuned models into a single multi-task model. Most existing model merging approaches follow the Task Arithmetic paradigm, which decomposes fine-tuned weights into pre-trained parameters and task vectors, and performs merging exclusively in the task-vector space. The effectiveness of this paradigm implicitly relies on the assumption that task-specific knowledge is encoded solely within task vectors. We argue that this assumption generally does not hold due to the intrinsic task preferences of pre-trained models. Specifically, we identify Load-Bearing Wall (LBW) dimensions, namely some task-critical knowledge that remains embedded in the pre-trained weights rather than being fully transferred into task vectors. We characterize LBW dimensions from both scalar-weight and subspace perspectives, thereby covering the major paradigms of existing model merging methods. Our analysis reveals that, by ignoring LBW dimensions, task-vector-based approaches fail to fully resolve task conflicts and may inadvertently damage task-specific knowledge encoded in the pre-trained model, leading to degradation. To address this issue, we propose PACT, which preserves the anchored task-specific cores (i.e., LBW dimensions) within task vectors by aligning their orthogonal complements with the subspace of the pre-trained weights. These aligned subspace components are then removed from the task vectors before applying existing model merging algorithms. Furthermore, we develop an efficient variant based on randomized SVD to improve scalability. PACT can be seamlessly integrated with existing methods. Extensive experiments across multiple benchmarks demonstrate that PACT consistently enhances mainstream model merging approaches and establishes new state-of-the-art performance.

14.
arXiv (CS.AI) 2026-06-18

A Technical Taxonomy of LLM Agent Communication Protocols

arXiv:2606.19135v1 Announce Type: cross Abstract: As large language models (LLMs) advance and multi-agent systems aim to overcome the limits of standalone agents, robust communication protocols are becoming essential infrastructure for distributed agent networks. Nonetheless, the fragmented protocol landscape presents a significant interoperability challenge. This study develops a technical taxonomy to classify and analyze LLM agent communication protocols. Following an established iterative method, we defined the taxonomy's purpose, meta-characteristic, and ending conditions, then performed five iterations, three empirical-to-conceptual and two conceptual-to-empirical, on nine actively maintained open-source protocols with demonstrable adoption. The taxonomy comprises five dimensions: counterparty, payload, interaction state, discovery mechanism, and schema flexibility. Classification reveals recurring architectural patterns: all sampled agent-to-agent protocols combine hybrid payloads with session-state persistence; most protocols support multiple predefined schemas, and two negotiate schemas at runtime, indicating a trend toward schema flexibility; decentralized discovery remains rare. Analysis suggests short-term convergence pressure toward protocols unifying agent-to-agent and agent-to-context (tool and data) communication. Long-term, however, no single protocol is likely to maximize versatility, efficiency, and portability simultaneously. The field will more likely evolve toward a federated, layered protocol stack. The framework guides protocol selection and highlights open research gaps such as privacy and policy enforcement.}

15.
arXiv (CS.LG) 2026-06-18

The Illusion of Improvement: Reject Inference Strategies in Credit Scoring

arXiv:2606.18479v1 Announce Type: new Abstract: Reject inference methods are widely used to mitigate survival bias in credit scoring, yet their effectiveness remains poorly understood. We systematically evaluate several such methods and uncover a structural failure mode: in a natural retraining cycle, models whose accuracy improves while recall collapses create an illusion of improvement that leads practitioners to believe the system is getting better when, in fact, its rejection quality – the ability to correctly screen out defaulters – is deteriorating. We then propose a controlled exploration strategy that breaks the feedback loop without statistical assumptions: the lender deliberately approves a fraction of rejected applicants and observes their true outcomes. We show that accuracy and rejection quality give opposite recommendations on whether to explore: accuracy favors no exploration, while rejection quality improves with it, confirming that standard evaluation metrics are misleading under selection bias. Even minimal exploration rates (2–5\%) prove sufficient in our experiments to diagnose the severity of the feedback loop at near-zero cost. Our findings are consistent across two machine learning methods and three real-world datasets, and suggest that standard evaluation protocols are inadequate for assessing models trained under survival bias.

16.
arXiv (CS.LG) 2026-06-15

Adaptive Oscillatory-State Alignment for Time Series Forecasting

arXiv:2606.06010v2 Announce Type: replace Abstract: Long-term time series forecasting benefits from inductive biases that expose recurring temporal structure. Existing periodic forecasting methods typically model recurrence through predefined periods, global spectral components, or fixed learnable templates. However, real-world temporal dynamics are rarely rigidly periodic: around a nominal cycle, oscillatory behavior often exhibits non-rigid periodicity (NRP), where cycle magnitude, cycle alignment, and local cycle duration vary over time. Under these conditions, fixed-template periodic modeling can become fundamentally mismatched to the underlying temporal states. We propose AOSNet, a Hilbert-guided forecasting framework that reformulates periodic forecasting from fixed template matching to adaptive oscillatory-state alignment. AOSNet extracts analytic-signal descriptors from both the observed sequence and a learnable global oscillatory prior, then adaptively aligns local states through a descriptor-conditioned gate that selectively preserves reliable observations while softly correcting mismatched regions. The learned prior serves not as a rigid repeated template but as a flexible oscillatory reference interpreted through local state dynamics. Experiments on eight public benchmarks and two cloud workload traces demonstrate leading or highly competitive accuracy with a compact model size and low inference latency, supporting repeated forecasting settings such as capacity planning and autoscaling. Controlled synthetic studies that isolate cycle-magnitude and cycle-alignment variation and combine them with cycle-duration changes show that the advantage of oscillatory-state alignment increases as NRP intensifies.

17.
bioRxiv (Bioinfo) 2026-06-12

ProMiSE: Protein Multi-State Evaluation Benchmark in Biological Contexts

Proteins are inherently dynamic, with biological functions often emerging from transitions between multiple conformational states. While recent breakthroughs have largely addressed the static structure prediction problem, no systematic benchmark exists to demonstrate how well current models capture functionally relevant dynamics. We introduce ProMiSE, the first benchmark that provides both a dataset and an evaluation scheme, based on native biological assemblies and integrating major conformational change mechanisms - intrinsic, ligand-induced, and protein-induced - within a single curated dataset. We conducted a comprehensive evaluation of state-of-the-art structure prediction models, including AlphaFold3 and recent generative approaches. Our findings reveal that current models exhibit a limited ability to sample intrinsic multi-states and are often insensitive to biological context in induced scenarios. Internal representation analysis suggests that training-data exposure can shift predictions toward dominant conformational states over alternative biologically relevant states, primarily at the structure module. In contrast, results from BioEmu indicate that reducing decoding-stage bias can substantially improve multi-state sampling without major changes to upstream pair representations.

18.
medRxiv (Medicine) 2026-06-10

A risk-of-contagion index using a Bayesian based model for the COVID-19 epidemic in Mexico

During the COVID-19 pandemic, limited testing capacity and reporting delays complicated epidemic surveillance and decision-making in Mexico. We calibrated textit{covidestim}, a Bayesian nowcasting model, to estimate the total SARS-CoV-2 infections from reported cases and deaths using Mexican surveillance data. Disease-progression distribution priors were calibrated using Mexico City records and validated through comparisons with national seroprevalence surveys, hospitalization data, and annual reported severe-case rates across all states. Using the reconstructed estimates of active infections, we implemented an event-based risk framework that quantifies the probability of encountering at least one infectious individual in gatherings of different sizes. This probability was subsequently translated into a four-level epidemiological traffic-light indicator and computed at both state and municipality levels. The resulting estimates revealed substantial spatial heterogeneity that is obscured by state-level aggregation, particularly in states with marked differences between urban and rural municipalities. To evaluate consistency with public-health indicators, we compared the proposed risk classification with the official Mexican epidemiological traffic-light system, considering interpretable gathering sizes relevant to public-health decision making. Weekly reports derived from this framework were delivered to policymakers in the State of Queretaro in Mexico, as an anticipation tool for school reopening and public-space management. This demonstrates that this Bayesian reconstruction of infections combined with event-based risk metrics can provide an interpretable and generalizable municipality-level complement to routine surveillance systems, particularly in regions with limited testing capacity and heterogeneous local transmission dynamics.

19.
arXiv (CS.AI) 2026-06-17

DecoSearch: Complexity-Aware Routing and Plan-Level Repair for Text-to-SQL

arXiv:2606.17821v1 Announce Type: new Abstract: Large Language Models (LLMs) have demonstrated remarkable capabilities in translating natural language to SQL, yet existing methods still falter on complex queries requiring multi-step, data-aware reasoning. We introduce DecoSearch, a training-free framework that addresses this by routing each query to the appropriate level of reasoning effort. A lightweight Schema Selector first prunes the full database schema to the relevant tables and columns. An LLM Judger then decides whether the question requires decomposition: straightforward questions follow a direct generation path and complex ones are escalated to a Directed Acyclic Graph (DAG) of atomic sub-questions, each solved by a targeted SQL generation step. A RAG component grounds the decomposer with semantically similar training examples, and a Topology Refiner restructures the reasoning plan when execution failures signal a flawed decomposition rather than a fixable SQL error. DecoSearch achieves 70.53% execution accuracy on BIRD and 88.31% on Spider with a DeepSeek backbone, surpassing all training-free baselines while consuming an order of magnitude fewer tokens than competing methods. It also functions as a model-agnostic wrapper, consistently improving fine-tuned SQL generation backbones without any modification to the pipeline.

20.
arXiv (CS.CV) 2026-06-17

PhaseWin: An Efficient Search Algorithm for Faithful Visual Attribution

Visual attribution is a fundamental tool for interpreting modern vision and vision-language models, particularly when their decisions must be inspected, diagnosed, or audited. Its goal is to explain how a model's decision depends on local regions of the visual input, typically by assigning an importance ordering over candidate image regions. Given an image partitioned into $n$ regions, faithful attribution can be cast as an ordered subset-search problem, in which progressively inserting the selected regions should recover the target model response as early as possible. Exhaustive search over region subsets incurs exponential cost, while the widely used greedy search still requires a quadratic number of model evaluations, because every selection step rescores all remaining candidates. We propose PhaseWin, an efficient subset-search algorithm for faithful visual attribution. PhaseWin reorganizes greedy region selection into a phased window-search procedure: rather than re-evaluating the full candidate set at every step, it alternates between global candidate screening, adaptive pruning, and localized window refinement, while preserving the essential region-ranking behavior of greedy search. We analyze PhaseWin under monotone evidence-accumulation conditions and show that, under feature-level structural assumptions, it attains controllable linear evaluation complexity together with near-greedy faithfulness guarantees. Extensive experiments on image classification, object detection, visual grounding, and image captioning show that, among all compared attribution methods, PhaseWin reaches high faithfulness with the fewest forward passes, empirically realizing the predicted reduction from $O(n^2)$ to $O(n)$. The code is available at https://github.com/Qihuai27/phasewin-va.

21.
bioRxiv (Bioinfo) 2026-06-15

DAQplugin: Deep Learning based Real-time Model Evaluation Plugin for ChimeraX

Although an increasing number of protein structures are determined by cryogenic electron microscopy (cryo-EM), protein structure modeling frequently suffers from residue misassignments and sequence register shifts, particularly in regions with ambiguous density. Here, we present DAQplugin, a ChimeraX plugin that performs real-time evaluation of protein models against cryo-EM density maps using the deep-learning-based residue-wise model quality (DAQ) score. Unlike existing validation tools that are typically applied after model construction, DAQplugin enables real-time deep-learning-based validation during model building and refinement. To our knowledge, DAQplugin is the first tool that provides real-time deep-learning based validation of protein models for cryo-EM map within an interactive modeling environment. In addition to identifying potential modeling errors, DAQplugin also provides guidance for correcting sequence register shifts by suggesting alternative residue placements along the backbone. The computation in this plugin is designed to run efficiently on general CPUs without requiring GPU hardware. Using DAQplugin, users can perform deep-learning-based validation on standard laptops during interactive model building, model-map fitting, and refinement. DAQplugin is able to facilitate more accurate interpretation of cryo-EM density maps and improve the reliability assessment of protein structure models.

22.
Nature (Science) 2026-06-10

Molecular glue degraders of HuR suppress BRAF-mutant colorectal cancer

Authors:

BRAF gain-of-function mutations, particularly BRAF(V600E), affect roughly 10% of all patients with colorectal cancer (CRC), and portend poor prognosis with limited therapeutic interventions. BRAF inhibitors such as encorafenib are ineffective due to MAPK pathway reactivation driven by BRAF dimerization. Combined inhibition of BRAF and EGFR, although approved therapies, results in short survival benefits and frequent treatment resistance and relapse1–3. Here, through rational chemical library design coupled with parallel proteomic screening, we identified dHuR as a molecular glue degrader of human antigen R (HuR), an RNA-binding protein that drives tumour growth, invasion and therapy resistance. dHuR binds to the CRBN ubiquitin ligase to create a unique benzofuran-tethered composite surface to recruit HuR as a neosubstrate by engaging its β-hairpin G-loop degron, as revealed by the cryo-electron microscopy structure of the ternary complex. dHuR abrogated BRAF expression by inducing its exon 18 skipping, and demonstrated superior suppression of BRAF-mutant CRC tumours including those gaining resistance to BRAF inhibitors. Finally, we performed kinome library CRISPR screening and revealed that inactivation of EGFR or MEK enhanced dHuR cytotoxicity, thus establishing a combinatorial strategy to treat patients with refractory BRAF-mutant CRC. Molecular glue degraders of the RNA-binding protein HuR have therapeutic potential for BRAF-mutant cancers.

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

Integral Formulation of QENDy for Robust Nonlinear System Identification

arXiv:2606.11629v1 Announce Type: cross Abstract: This manuscript proposes an integral formulation of the newly defined quadratic embedding method for identifying nonlinear systems (QENDy). In the original algorithm, trajectory data points along with their time derivatives are used. Methods for calculating time derivatives make the algorithm sensitive to noise. Our integral formulation does not use the time derivatives. This results in a more robust method to learn the dynamics.

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

MemPO: Self-Memory Policy Optimization for Long-Horizon Agents

arXiv:2603.00680v4 Announce Type: replace Abstract: Long-horizon agents face the challenge of growing context size during interaction with environment, which degrades the performance and stability. Existing methods typically introduce the external memory module and look up the relevant information from the stored memory, which prevents the model itself from proactively managing its memory content and aligning with the agent's overarching task objectives. To address these limitations, we propose the self-memory policy optimization algorithm (MemPO), which enables the agent (policy model) to autonomously summarize and manage their memory during interaction with environment. By improving the credit assignment mechanism based on memory effectiveness, the policy model can selectively retain crucial information, significantly reducing token consumption while preserving task performance. Extensive experiments and analyses confirm that MemPO achieves absolute F1 score gains of 25.98 over the base model and 7.1 over the previous SOTA baseline, while reducing token usage by 67.58% and 73.12%. The code is released at https://github.com/TheNewBeeKing/MemPO.

25.
arXiv (CS.CL) 2026-06-24

What's Missing in Vision-Language Models? Probing Their Struggles with Causal Order Reasoning

Despite the impressive performance of vision-language models (VLMs) on downstream tasks, their ability to understand and reason about causal relationships in visual inputs remains unclear. Robust causal reasoning is fundamental to solving complex high-level reasoning tasks, yet existing benchmarks often include a mixture of reasoning questions, and VLMs can frequently exploit object recognition and activity identification as shortcuts to arrive at the correct answers, making it challenging to truly assess their causal reasoning abilities. To bridge this gap, we introduce VQA-Causal and VCR-Causal, two new benchmarks specifically designed to isolate and rigorously evaluate VLMs' causal reasoning abilities. Our findings reveal that while VLMs excel in object and activity recognition, they perform poorly on causal reasoning tasks, often only marginally surpassing random guessing. Further analysis suggests that this limitation stems from a severe lack of causal expressions in widely used training datasets, where causal relationships are rarely explicitly conveyed. We additionally explore fine-tuning strategies with hard negative cases, showing that targeted fine-tuning can improve model's causal reasoning while maintaining generalization and downstream performance. Our study highlights a key gap in current VLMs and lays the groundwork for future work on causal understanding.