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

Leave-One-Out-, Bootstrap- and Cross-Conformal Anomaly Detectors

arXiv:2402.16388v4 Announce Type: replace-cross Abstract: The need for uncertainty quantification in anomaly detection systems has become increasingly important. In this context, effectively controlling Type I error rates without inflating Type II error rates in these systems can build trust and reduce costs associated with false discoveries. The field of conformal anomaly detection emerges as a promising approach for providing respective statistical and finite-sample validity guarantees through model calibration. However, reliance on calibration data imposes practical limitations, especially in low-data regimes. In this work, we formally define and evaluate leave-one-out-, bootstrap-, and cross-conformal methods for conformal anomaly detection, building on methods from the field of conformal prediction. Looking beyond the classical split-conformal approach, we show that derived methods for calculating resampling-conformal $p$-values offer a practical compromise between the data efficiency of full-conformal (transductive) approaches and the computational efficiency of split-conformal (inductive) methods. We validate derived methods and quantify their improvements for a range of one-class classifiers and datasets.

02.
arXiv (CS.CL) 2026-06-16

Building Customer Support AI Agents at 100M-User Scale: An Evaluation-Driven Framework

The rapid rise in LLM capabilities has made AI agents increasingly viable across a broad range of tasks. Among the most promising applications is building production-ready customer-facing agents, a challenge that demands coordinated excellence in evaluation methodology, context engineering, training, and online measurement. Yet these critical pillars are typically developed in isolation, creating blind spots that only surface after deployment. In this paper, we present a unified framework that bridges offline development with online impact for customer support AI agents at Nubank, a company with 100M+ users. Our approach integrates several key components: (1) structured context engineering tailored to customer support agents, (2) systematic human-in-the-loop prompt iteration, (3) rigorous LLM judge evaluation with measured inter-rater agreement and GEPA optimization for consistency, and (4) ideation-to-production validation. A central insight is that evaluation-pipeline quality directly determines iteration velocity. We present results from five production deployments spanning distinct domains: card delivery, debt management, credit-limit support, card management, and product explanation. These deployments deliver consistent customer-satisfaction gains while substantially accelerating iteration. In our card-delivery deployment, large-scale A/B testing yields a 37 percentage-point improvement in AI transactional Net Promoter Score and a 29 percentage-point gain in self-service rate over prior agent variants, alongside a strong correlation between offline simulation metrics and online outcomes, demonstrating that eval-driven development reliably predicts production impact. On most use cases, AI satisfaction reaches within a few percentage points of expert human agents.

03.
arXiv (CS.LG) 2026-06-12

Estimating Individualized Treatment Effects in Acute Ischemic Stroke with Causal Transformation Models (TRAM-DAG): A Multi-Centre Observational Study with External RCT Validation

arXiv:2606.12623v1 Announce Type: cross Abstract: Personalized medicine in acute ischemic stroke requires moving beyond average treatment effects (ATE) to individualized treatment effect (ITE) estimates to support treatment decisions. In acute ischemic stroke, mechanical thrombectomy has been shown to be more effective on average than lysis in randomized controlled trials (RCTs), such as the MR CLEAN study. We aim to identify which individual patients benefit most from mechanical thrombectomy compared to lysis. The outcome of interest is the modified Rankin Scale (mRS) at three months, an ordinal measure of functional disability (0: no symptoms, 6: death). We demonstrate that causal transformation models on directed acyclic graphs (TRAM-DAG) can be used for ITE estimation after being fitted on observational MAGIC multi-center stroke patient data. To ensure comparability with the MR CLEAN population, which we use for validation, we train the TRAM-DAG on a MAGIC sub-population with NIHSS at admission >= 6, corresponding to one inclusion criterion of MR CLEAN. The fitted model is then used to estimate ITEs for stroke patients in the MR CLEAN population. While these ITE estimates cannot be confirmed experimentally, we show that their average is consistent with the trial's reported ATE. Furthermore, the ITE estimates correctly rank trial patients by their observed frequency of a good outcome (mRS at three months

04.
arXiv (CS.CL) 2026-06-18

LegalWorld: A Life-Cycle Interactive Environment for Legal Agents

Civil litigation is inherently a life-cycle process: what a lawyer drafts on day one constrains what unfolds at trial months later. Yet existing legal benchmarks evaluate isolated subtasks, and prior legal-agent simulators reinitialize each scenario from shared ground truth, leaving cross-stage causal dependencies unmodeled. We present LegalWorld, a life-cycle interactive environment that models Chinese civil litigation as a causally connected state chain of five stages (seven sub-scenarios), grounded in 75,309 paired Chinese civil judgments. We pair it with reusable infrastructure (local memory, global case memory, a Skill/Tool library) that keeps each dispute consistent across its full life cycle. Building on this environment, we construct LongJud-Bench to evaluate agent capability across all five connected stages. 18,992 ratings from 217 legal-background evaluators confirm that LegalWorld trajectories are procedurally faithful and role-consistent; and a capability-level cross-model evaluation reveals sharp divergences that aggregate scores cannot expose, with no single backbone leading across consultation, drafting, and courtroom advocacy. Detailed resources will be released publicly.

05.
arXiv (CS.CL) 2026-06-12

RogueAI: A Reverse Turing Test for Detecting Licensed AI Deception in Dialogue

The original Turing Test asks a human judge to distinguish a machine from a person through dialogue. Three quarters of a century later, conversational systems pass this test in casual settings; the interesting epistemological question has shifted. We argue that the relevant modern variant asks not whether a dialogue partner is artificial, but whether it can be trusted. We present RogueAI, an interactive webapp that operationalizes this revisited test as a one-on-two interrogation game: a human player questions two indistinguishable Large Language Model agents, knowing that exactly one of them has been licensed to deceive within a shared fictional scenario. The player's task is to identify the deceptive agent and "shut it off" before a turn budget is exhausted. We further introduce AutoRogueAI, a procedural extension in which players co-design a custom scenario with a narrator agent that secretly chooses its own deception strategy. We describe the framing, sketch the abstract architecture and gameplay loop, and situate the artifact within recent work on LLM deception, social-deduction benchmarks, and scalable oversight via debate. A three-day pilot deployment (467 initiated sessions, 415 completed, 1876 interaction turns in Italian) provides early feasibility evidence and surfaces a concrete tension: the deceptive agent carries a reliable, locally-present linguistic signature - differential helpfulness, brevity, hedging - that a simple heuristic exploits at 75.6% accuracy, yet human players achieved only 56.6%, consistent with ignoring the most diagnostic signal entirely. We discuss what this gap implies for the artifact's use as a data-collection vehicle, a teaching tool, and an evaluation harness for honesty-trained models.

06.
bioRxiv (Bioinfo) 2026-06-11

STITCH links cellular morphology and gene expression in spatial transcriptomics

In situ spatial (ISS) sequencing can uncover co-variation between cellular morphology and gene expression in vivo. However, a principled and interpretable mathematical representation of morphology has not yet been applied in this context. In particular, current deep learning-based representations of cell images confound a cell's shape with its size. We present an interpretable representation of cellular boundary contours, based on tangent principal component analysis (TPCA) in a Kendall shape manifold, that captures size-independent contour shape features. This approach successfully recovers shape-perturbing genes in an RNAi screen than a previous metric geometry-based approach. We build on TPCA to develop STITCH (Shape-TranscriptomIc Correlation and Harmonization), an approach to reveal covariation between cell morphology with gene expression in ISS datasets. In a Xenium dataset, STITCH outperforms a deep learning-based approach in both recovering the layered organization of keratinocytes and a spatial gradient in nuclear eccentricity. Across samples in a melanoma CosMx dataset, STITCH reproducibly associates elongated and triangular fibroblasts with proximity to malignant cells and myofibroblast-like transcriptional program. Finally, STITCH independently recovers a known link between mesenchymal-like malignant cell states and increased cell area in two melanoma cohorts. STITCH can thus yield interpretable morphology-transcriptome relationships across cell types, patients, and spatial transcriptomics platforms.

07.
arXiv (CS.CV) 2026-06-16

NEXUS: Neural Energy Fields for Physically Consistent Contact-Rich 3D Object Dynamics

Physics-grounded video generation requires controllable 3D object dynamics that remain physically consistent under contact, deformation, and external forcing. Existing trajectory-based methods often model isolated physical effects, making it difficult to compose conservative and non-conservative dynamics in contact-rich 3D scenes. We present NEXUS, a neural energy-field framework for contact-rich 3D object dynamics. NEXUS represents each object as a structural graph and constructs dynamic object-object and object-environment contact graphs. Inspired by Hamiltonian Neural Networks, NEXUS formulates motion through scalar energy and dissipation terms rather than directly predicting states or accelerations. Conservative effects, including gravity and elastic deformation, are composed as additive energy terms, while non-conservative effects such as damping and impact-induced energy loss are modeled with learned Rayleigh-style dissipation. Forces are derived by differentiating the energy and dissipation functions and rolled out with a multi-substep semi-implicit integrator. Across controlled trajectory benchmarks, NEXUS improves long-horizon accuracy over representative learned and physics-structured dynamics baselines under varying mechanical properties and physical-effect compositions. We further show that NEXUS trajectories provide effective guidance for contact-rich video generation, improving physical plausibility while maintaining competitive visual quality.

08.
arXiv (quant-ph) 2026-06-17

Emergent de Sitter Space and Non-Unitary Tensor Networks from Non-Hermitian Quantum Criticality

arXiv:2606.17983v1 Announce Type: new Abstract: Extending the holographic principle to de Sitter (dS) spacetimes remains one of the most vital open frontiers in quantum gravity, where a microscopic, bottom-up tensor-network framework that relates boundary quantum data to emergent de Sitter spacetime is still lacking. In this work, we first show the emergence of de Sitter spacetime from boundary entanglement by formulating a non-unitary continuous multi-scale entanglement renormalization ansatz (cMERA) for a concrete non-Hermitian critical fermion chain. Within this emergent spacetime, we analyze the associated geodesics and show that they act as extremal Ryu-Takayanagi (RT) surfaces undergoing a smooth timelike-to-null transition. Remarkably, we demonstrate that this continuum trajectory dictates a distinct tensor-network architecture in which the bond-counting contribution naturally truncates at the discrete timelike-to-null transition toward the deep infrared. In the resulting architecture, the null ray along the horizon is represented by zero-cost links, since the associated cut severs no tensor legs. This network structure successfully reproduces the logarithmic scaling of non-unitary critical entanglement entropy, offering a bond-counting picture for the de Sitter RT formula. Our results provide the long-sought dS/(c)MERA correspondence at the level of both emergent spacetime and discrete holographic entanglement.

09.
arXiv (CS.CL) 2026-06-18

Are LLMs Ready to Assist Physicians? PhysAssistBench for Interactive Doctor-Patient-EHR Assistance

The most plausible near-term role of medical LLMs is to assist rather than replace physicians, yet current evaluations often test isolated capabilities: clinical knowledge, EHR system interaction, or patient communication. Physician assistance instead requires coordinating these capabilities within the same interaction, where physicians issue underspecified requests, patients describe symptoms ambiguously, and EHR systems demand precise tool use. We introduce PhysAssistBench, a benchmark for interactive doctor-patient-EHR assistance. Built from real MIMIC-IV cases, PhysAssistBench uses a scalable pipeline to construct agentic patients: interactive, record-grounded agents that turn static EHR records into multi-turn clinical scenarios while preserving clinical factuality. PhysAssistBench provides a curated bilingual evaluation set of 1,296 manually reviewed and physician-validated turns. Experiments with leading LLMs show that current models remain unreliable in this setting, which exposes a key bottleneck for clinical LLMs: reliable assistance requires coordination across knowledge, communication, and systems, not isolated gains in any of them.

10.
arXiv (CS.AI) 2026-06-18

Practical Anonymous Two-Party Gradient Boosting Decision Tree

arXiv:2605.26903v2 Announce Type: replace-cross Abstract: Structured data is well handled by gradient-boosted decision trees (GBDT), which are usually trained on vertically partitioned features across mutually distrustful parties. High speed and interpretability make GBDTs popular in finance and healthcare, where neural networks may fall short. Enabling secure computation for GBDTs poses unique challenges, requiring secure record alignment for comparison. Relying on private set intersection (PSI) is a de facto approach. Mistaking PSI for a safety measure actually exposes which record identifiers (IDs) are shared between the datasets. Although circuit-PSI could help, it is costly for generic uses. New ideas are needed to efficiently train in a "dark forest". Aiming to hide the IDs, we initiate the study of anonymous GBDT training on split data held by two parties. Dual circuit-PSI in our design lets the parties alternate as receiver to run pick-then-sum over local features. Via oblivious programmable pseudorandom functions, we propagate circuit-PSI outputs as shared state across runs. Avoiding universal alignment, we resolve the neglected dilemma that ID hiding incurs a cost that scales with domain size. Next, we halve the cost of ciphertext packing used to convert single-instruction multiple-data homomorphic encryption from (ring) learning with errors in prior secure GBDT (Usenix Security' 23) and related secure machine-learning computations. Comparative experiments show our protocol remains competitive with leaky approaches in efficiency. Enabling ID-hiding aggregation, our techniques can extend to other vertically partitioned analytics.

11.
arXiv (CS.CL) 2026-06-24

Block-wise Codeword Embedding for Reliable Multi-bit Text Watermarking

Recent multi-bit watermarking methods for large language models (LLMs) prioritize capacity over reliability, often conflating decoding with detection. Our analysis reveals that existing ECC-based extractors suffer from catastrophic false positive rates (FPR), and applying rejection thresholds merely collapses detection sensitivity (TPR) to random guessing. To resolve this structural limitation, we propose BREW (Block-wise Reliable Embedding for Watermarking), a framework shifting the paradigm to designated verification. BREW employs a two-stage mechanism: (i) blind message estimation via independent block voting, followed by (ii) window-shifting verification that rigorously validates the payload against local edits. Experiments demonstrate that BREW achieves a TPR of 0.965 with an FPR of 0.02 under 10% synonym substitution, demonstrating that the high-FPR issue is not an inherent trade-off of multi-bit watermarking, but a solvable structural flaw of prior decoding-centric designs. Our framework is model-agnostic and theoretically grounded, providing a scalable solution for reliable forensic deployment.

12.
arXiv (CS.LG) 2026-06-17

When Dynamics Models Read the Wrong Time Steps: Label-Free Event Credit Re-Anchoring for Robust Global Readouts

Authors:

arXiv:2606.17572v1 Announce Type: new Abstract: Learned dynamics models often answer global physical questions, such as fault severity or impact stiffness, by pooling a per-step feature sequence into one readout vector. This sequence-to-global interface creates an under-studied temporal credit problem: with only trajectory-level supervision, a model can predict accurately in training conditions while reading from abundant smooth correlates rather than the brief physical events that determine the target. We call this failure temporal credit dilution. It is not exposed by the training loss and is not removed by standard physics-informed residuals, because the error lies in where the global readout assigns functional credit. We introduce Credit-in-Event, an interface-level probe for measuring how much pooled credit lands on event steps, and prove in closed form that a pooled linear reader routes credit to a spurious background channel as the event fraction shrinks. We then propose CREST, a training-free and label-free readout that estimates a transient event core from learned features and re-anchors the pooled representation through event-versus-rest contrast. Across simulated gear and impact systems, recurrent and attention encoders, and public bearing vibration data, CREST reduces out-of-distribution error while restoring event credit. Ablations show that stable-step selection and receptive-field shrinking fail, confirming that the gain comes from event-core credit re-anchoring rather than a generic locality or stability prior.

13.
arXiv (CS.CL) 2026-06-15

Efficiency-Performance Trade-offs in Neural Speaker Diarization via Structured Pruning and Low-Bit Quantization

Streaming speaker diarization is crucial for time-critical medical dispatch, but deploying it on resource-constrained hardware requires smaller, faster models. Using SIMSAMU, a dataset of simulated medical-dispatch conversations, we evaluate streaming behavior before compressing the segmentation model with pruning and low-bit quantization. We characterize performance across a range of streaming latency budgets and find that additional buffering is not consistently beneficial, while very low-latency operating points can substantially degrade performance. Our study shows that model compression trades performance for memory footprint, and we highlight an operating point where FP16 reduces model size by half with essentially unchanged real-time factor, at a cost of a 40\% relative DER increase against the baseline. This work characterizes the trade-offs for real-time deployment and contributes to speech technology that can enable reliable human communication in time-critical contexts.

14.
arXiv (CS.CV) 2026-06-16

Learning Fine-Grained Correspondence with Cross-Perspective Perception for Open-Vocabulary 6D Object Pose Estimation

Open-vocabulary 6D object pose estimation empowers robots to manipulate arbitrary unseen objects guided solely by natural language. However, a critical limitation of existing approaches is their reliance on unconstrained global matching strategies. In open-world scenarios, trying to match anchor features against the entire query image space introduces excessive ambiguity, as target features are easily confused with background distractors. To resolve this, we propose Fine-grained Correspondence Pose Estimation (FiCoP), a framework that transitions from noise-prone global matching to spatially-constrained patch-level correspondence. To systematically eliminate background interference, FiCoP first employs an object-centric disentanglement step to isolate the target from macro-level environmental noise. Building upon this localized region, our core methodological innovations are twofold. Firstly, a Cross-Perspective Global Perception (CPGP) module is proposed to fuse dual-view features, establishing structural consensus through explicit context reasoning and text-guided semantic injection. Secondly, we design a Patch Correlation Predictor (PCP) that leverages a patch-to-patch correlation matrix as a structural prior. This generates a precise block-wise association map, acting as a spatial filter to enforce fine-grained, noise-resilient matching. Experiments on the REAL275 and Toyota-Light datasets demonstrate that FiCoP improves Average Recall by 8.0% and 6.1%, respectively, compared to the state-of-the-art method, highlighting its capability to deliver robust and generalized perception for robotic agents operating in complex, unconstrained open-world environments. The source code will be made publicly available at https://github.com/zjjqinyu/FiCoP.

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

Optimizing Health Coverage in Ethiopia: A Learning-augmented Approach and Persistent Proportionality Under an Online Budget

arXiv:2509.00135v2 Announce Type: replace Abstract: As part of nationwide efforts aligned with the United Nations' Sustainable Development Goal 3 on Universal Health Coverage, Ethiopia's Ministry of Health is strengthening health posts to expand access to essential healthcare services. However, only a fraction of this health system strengthening effort can be implemented each year due to limited budgets and other competing priorities, thus the need for an optimization framework to guide prioritization across the regions of Ethiopia. In this paper, we develop a tool, Health Access Resource Planner (HARP), based on a principled decision-support optimization framework for sequential facility planning that aims to maximize population coverage under budget uncertainty while satisfying region-specific proportionality targets at every time step. We then propose two algorithms: (i) a learning-augmented approach that improves upon expert recommendations at any single-step; and (ii) a greedy algorithm for multi-step planning, both with strong worst-case approximation estimation. In collaboration with the Ethiopian Public Health Institute and Ministry of Health, we demonstrated the empirical efficacy of our method on three regions across various planning scenarios.

16.
Nature (Science) 2026-06-22

Isotopic evidence for a cold and distant origin of 3I/ATLAS

Interstellar objects provide the only directly observable samples of icy planetesimals formed around other stars, and can therefore provide insight into the diversity of physical and chemical conditions occurring during exoplanet formation1−3. Here we report isotopic measurements of the interstellar comet 3I/ATLAS, which reveal an elemental composition unlike any Solar System body. The water in 3I/ATLAS is enriched in deuterium, at a level of D/H = (0.98 ± 0.06)%, which is more than an order of magnitude higher than in known comets, while its range of 12C/13C ratios (141–191 for CO2 and 123–172 for CO) exceeds typical values found in the Solar System, as well as nearby interstellar clouds and protoplanetary disks. Such extreme isotopic signatures indicate formation at temperatures  ≲ 30 K in a relatively metal-poor environment. When interpreted with respect to models for Galactic chemical evolution, the carbon isotopic composition implies that 3I/ATLAS may have accreted as long ago as 12 billion years, following a period of intense, early star formation. 3I/ATLAS thus represents a preserved fragment of an ancient planetary system.

18.
arXiv (CS.LG) 2026-06-12

Adaptive generative moment matching networks for improved learning of dependence structures

arXiv:2508.21531v2 Announce Type: replace-cross Abstract: An adaptive bandwidth selection procedure for the mixture kernel in the maximum mean discrepancy (MMD) for fitting generative moment matching networks (GMMNs) is introduced, and improved learning of copula random number generators is demonstrated. Based on the relative error of the training loss, the number of kernels is increased during training; additionally, the relative error of the validation loss is used as an early stopping criterion. While training time remains similar, adaptively training GMMNs (AGMMNs) significantly increases training performance, which is shown based on validation MMD trajectories, samples and validation MMD values. Superiority of AGMMNs over GMMNs and parametric copula models is also demonstrated in terms of three applications. First, convergence rates of estimators based on quasi-random versus pseudo-random samples from copulas are investigated in dimensions as large as 100 for the first time. Second, replicated validation MMDs, as well as Monte Carlo and quasi-Monte Carlo applications demonstrate the improved training of AGMMNs for a copula model implied by the 50 constituents of the S&P 500 index after deGARCHing. Last, both the latter dataset and 50 constituents of the FTSE 100 are used to demonstrate that the improved training of AGMMNs indeed translates to an improved model prediction.

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

Universal Image Restoration via Internalized Chain-of-Thought Reasoning

Image restoration seeks to recover high-quality images from degraded inputs but becomes highly ill-posed under complex, mixed degradations. While unified all-in-one models are common, their performance declines as degradation complexity increases. Recent works adopt Chain-of-Thought (CoT) reasoning for multi-round restoration using specialized modules. However, this approach faces two key limitations: (i) increased computational cost due to multi-step processing, and (ii) weak modeling of interactions between degradations during stepwise inference. We introduce CoTIR, a universal image restoration framework that internalizes CoT reasoning within a single model. Concretely, we view image restoration as a specialized subtask of image editing, which implies that a large-scale pre-trained editing model provides a more favorable optimization starting point. Building on this, we fine-tune the model for restoration and further encode structured CoT-style reasoning into the learning objective via a differentiable formulation inspired by Lagrangian optimization, enabling holistic restoration without chaining specialized restorers. To facilitate training and evaluation, we further present CoTIR-Bench, a large-scale benchmark comprising 5.2 million samples with CoT-style reasoning traces. Extensive experiments on CoTIR-Bench and broad real composite degradation scenes show that CoTIR achieves stronger perceptual quality and more competitive fidelity than both all-in-one models and multi-round restoration methods. The source code is available at https://github.com/gy65896/CoTIR.

20.
medRxiv (Medicine) 2026-06-22

AI-Assisted Longitudinal Analyses of Environmental and Psychosocial Determinants of Subjective Cognitive Difficulties

Authors:

Short-term environmental exposures have been linked to cognitive and behavioral outcomes, although many reported associations may reflect broader geographic and contextual differences. Using longitudinal data from the All of Us Research Program (2018–2024), we linked daily weather and air-pollution exposures to repeated attention-related and subjective cognitive outcomes. Associations were evaluated using pooled, fixed-effects, lagged, and event-study analyses. Additional machine-learning analyses were conducted to explore potential heterogeneity and latent psychosocial structure. Replication analyses were performed using the 2024 Behavioral Risk Factor Surveillance System (BRFSS). Several environmental exposure measures showed small associations with cognitive outcomes in pooled analyses, but most attenuated substantially after accounting for within-location temporal variation. Mediation, sensitivity, and machine-learning analyses yielded similar conclusions. In contrast, mental-health burden, loneliness, and social functioning were consistently associated with subjective cognitive difficulty and exhibited substantially larger effect sizes than environmental exposures. Similar patterns were observed in BRFSS. Exploratory AI-assisted analyses yielded findings broadly consistent with the primary longitudinal analyses. These findings suggest that short-term environmental perturbations may have limited associations with cognitive outcomes after accounting for within-location variation, whereas psychosocial factors appear to be more consistently associated with subjective cognitive burden.

21.
arXiv (CS.LG) 2026-06-17

Learning to Refine Hidden States for Reliable LLM Reasoning

arXiv:2606.17524v1 Announce Type: new Abstract: Large language models show strong reasoning ability, but their internal reasoning process can remain unstable in complex multi-step settings, where early hidden-state errors may propagate to incorrect predictions. We propose ReLAR, a reinforcement-guided latent refinement framework that iteratively updates hidden representations before decoding. ReLAR maintains a compact latent reasoning state and uses learned depth and action controllers to adaptively determine both the number and direction of refinement steps. The controllers are trained with a policy gradient objective based on step-wise likelihood improvement, enabling efficient input-dependent reasoning without explicit chain-of-thought generation. Experiments on medical, mathematical, multi-hop reasoning, and open-ended generation benchmarks show that ReLAR improves accuracy, generation quality, and reasoning stability with substantially lower inference overhead than explicit reasoning baselines.

22.
arXiv (CS.AI) 2026-06-24

JEDEL: Zero-Shot DNA-Encoded Library Design for Early-Stage Drug Discovery

arXiv:2606.23745v1 Announce Type: cross Abstract: We present JEDEL, a framework for generating synthesis-ready DNA-encoded libraries (DELs) directly from three-dimensional pharmacophore representations of active ligands. JEDEL is the first model to map pharmacophore interaction patterns to actionable, scalable synthesis instructions, enabling the design of targeted libraries comprising potentially millions of molecules. Unlike existing generative approaches that produce virtual compounds requiring downstream synthesis planning, JEDEL operates within the space of purchasable building blocks and validated reactions, ensuring that every output is experimentally realizable by construction. JEDEL learns a predictive alignment between pharmacophore geometry and molecular structure and decodes this into combinatorial synthesis routes at scale. Across 18 protein targets, it generates focused libraries that outperform random and diversity-based baselines in predicted binding affinity, pharmacophore recovery, and sample efficiency, without target-specific retraining. JEDEL enables a shift from virtual molecule generation to experimentally deployable library design.

23.
Nature (Science) 2026-06-17

Molecular basis of polyadenylated RNA fate determination in the nucleus

Authors:

Eukaryotic genomes generate a plethora of polyadenylated (pA+) RNAs1,2, which are packaged into ribonucleoprotein particles (RNPs). To ensure faithful gene expression, functional pA+ RNPs, including protein-coding RNPs, are exported to the cytoplasm, whereas transcripts within non-functional pA+ RNPs are degraded in the nucleus1–4. How cells distinguish these opposing fates remains unknown. The DExD-box ATPase UAP56 (also known as DDX39B) is a central component of functional pA+ RNPs, and promotes their docking to the nuclear pore complex-anchored TREX-25,6, which triggers transcript release from UAP56 to facilitate export7. Here we reveal that the poly(A) tail exosome targeting (PAXT) connection8 binds a TREX-2-like module, which releases pA+ RNAs from UAP56 for decay by the nuclear exosome. The core of this module consists of a LENG8–PCID2–SEM1 trimer, which we show is structurally and biochemically equivalent to the central GANP–PCID2–SEM1 trimer of TREX-2. Mutagenesis and transcriptomic data demonstrate that the nuclear fate of pA+ RNPs is governed by the contending actions of nucleoplasmic PAXT and nuclear pore complex-associated TREX-2, which interpret RNA-bound UAP56 as a signal for RNA decay or export, respectively. As RNA targets of PAXT are generally short and intron-poor, we propose an overall model for pA+ RNP fate determination whereby the distinct sub-nuclear localizations of PAXT and TREX-2 govern the degradation of short non-functional pA+ RNAs while allowing export of their longer and functional counterparts. Biochemical, structural and cell biological analyses reveal that UAP56 (DDX39B) assembles with a TREX-2–like module that redirects non-functional polyadenylated RNAs from export to degradation.

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

Matching Tasks to Objectives: Fine-Tuning and Prompt-Tuning Strategies for Encoder-Decoder Pre-trained Language Models

Prompt-based learning has emerged as a dominant paradigm in natural language processing. This study explores the impact of diverse pre-training objectives on the performance of encoder-decoder pre-trained language models across generation and question answering tasks, with a focus on commonsense knowledge retrieval and completion. We highlight the benefits of incorporating multiple objectives during both pre-training and fine-tuning stages. We introduce the Match Task to Objective (MTO) framework and methods for determining the appropriate objective for a given task. This framework offers automated methods to prepare task-related data for adaptation through unsupervised training, based on the identified objective. In the fine-tuning stage, we design novel templates that align with the objectives of the pre-training and adaptation stages. When aligned with task requirements, these strategies can achieve a performance gain of over 120\% compared to conventional methods in few-shot settings. They significantly outperform related works in few-shot settings and exceed the baseline even in full-dataset scenarios. Furthermore, we extend this approach to include prompt-tuning methodologies, providing guidance for more effective soft prompt engineering and optimization. Our strategies significantly enhance prompt-tuning performance as well. These insights hold substantial value, precisely guiding the selection and optimization of models customized for specific tasks. Code is available at https://github.com/puraminy/MTO/

25.
arXiv (CS.CL) 2026-06-11

Geometric Metrics and LLMs: What They Measure and When They Work

We present a systematic stress-test of geometric metrics for LLM evaluation. Rank-based geometric properties of internal representations have shown promise as reference-free quality signals, but the conditions under which they are reliable remain unclear. We evaluate eight commonly-used metrics: intrinsic-dimensionality estimators, spectral norms, and related quantities across six tester models (0.5-8B) and eight generators on contrasting tasks, separating genuine geometric signal from text-length effects and from what standard text statistics already capture. Three findings emerge. First, some metrics (notably Schatten Norm and MOM) mainly reflect output length, and their apparent discriminative power collapses once length is controlled. Second, geometric metrics add modest but real information beyond text statistics: combined with them, a classifier reaches 78% accuracy on 6-way generator identification versus 69% for text statistics alone. Third, rather than tracking a general notion of text quality, the metrics demonstrate only moderate association between the intrinsic-dimensionality and lexical diversity (RTTR). We give use-case-specific recommendations and identify failure detection as the most promising near-term application.