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01.
Nature Medicine 2026-06-15

Plasma proteomic signatures of cellular aging predict human disease

Authors:
Daisy Yi Ding↗

Aging is asynchronous across cells and organs. Here we tested whether plasma proteomics can be used to analyze cell type-specific aging. From analyses of over 7,000 plasma proteins measured in 60,542 individuals, we developed machine learning models to estimate the biological age of over 40 cell types spanning neuronal, immune, glial, endocrine, epithelial and musculoskeletal origins. We observed that 20–25% of individuals exhibited accelerated aging in a single cell type and 1–3% in 10 or more cell types. Cellular aging signatures were associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Individuals with the APOE4 genotype showed older astrocytes but younger macrophages compared to APOE3 carriers, whereas the APOE2 genotype had inverse associations. Moreover, extreme astrocyte aging tripled the risk of incident Alzheimer’s Disease in individuals with two APOE4 alleles, while youthful astrocytes reduced risk. Individuals with extremely aged compared to youthful skeletal myocytes exhibited a 12.7-fold higher risk of developing amyotrophic lateral sclerosis. In individuals who smoked, extreme respiratory epithelial cell aging was associated with a 58% higher lung cancer risk compared to smoking alone. Specific cellular vulnerabilities and cumulative cellular aging burden influenced survival, with youthful immune and neuronal cell types conferring protective effects. Finally, we developed a polycellular aging risk score that stratified mortality risk across cohorts and proteomics platforms. These findings establish a framework for quantifying human physiology at cellular resolution, revealing heterogeneous aging trajectories and their impact on disease susceptibility and resilience. The biological age of individual cell types can be evaluated using plasma proteomics, revealing diverse aging profiles across more than 40 cell types and links between the accelerated aging of specific cell types and disease.

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02.
medRxiv (Medicine) 2026-06-22

Virtual Responsive Neurostimulation Implantation: From Intracranial Connectivity to Optimized Lead Placement

Authors:
Feys↗Walsh↗K. G↗Nix↗K. C↗Josyula↗Sinha↗Lavelle↗S. B↗Wagenaar↗Michalak↗Morrell↗…

Responsive neurostimulation (RNS) is an implanted device that delivers direct brain stimulation for drug-resistant focal epilepsy. Individual responses are highly variable, and no validated framework exists to predict outcome or guide lead placement before implantation. We hypothesized that this variability is partly explained by lead placement in relation to patterns of functional connectivity in brain networks. Fourty-nine patients with drug-resistant focal epilepsy who underwent pre-implantation intracranial EEG (iEEG) and RNS implantation across three independent epilepsy centers were retrospectively studied. We developed a composite functional connectivity score, based on simple Spearman correlation, combining the standard deviation and kurtosis of interictal iEEG connectivity distributions to predict the response outcome in a training cohort (HUP, n=18) and validated in two independent cohorts (NYU, n=17; UCSF, n=14). We accounted for a spatial mismatch between iEEG and RNS electrodes with a distance-based correction. The score was extended to generate patient-specific 3D maps of predicted RNS efficacy across 200 simulated, or virtual RNS, lead configurations. Accuracy of the score in predicting clinical outcome was 72% at the group level, 61% at the individual patient level, and, after distance-based optimization, 100% in patients with RNS electrodes placed close to location of iEEG electrodes. Applied to the validation cohort, the same score reached 68% accuracy (71% balanced accuracy, 55% sensitivity, 88% specificity). The spatial combination of the scores at different SEEG contacts localization gives a spatial score for each patient. Responders showed significantly higher spatial scores than non-responders, supporting that actual RNS lead placement in responders was located in map-identified favorable regions. Interictal iEEG functional connectivity predicts individual RNS response across independent epilepsy centers, and patient-specific 3D maps derived from this biomarker could prospectively guide lead implantation toward favorable network regions, opening a promising avenue toward network-informed RNS surgical planning.

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04.
arXiv (quant-ph) 2026-06-17

Asymptotically Optimal Circuit Depth for Diagonal Unitary Synthesis and Compilation on Two-Dimensional Grids

Authors:
Chengzhuo Xu↗Xiao Chen↗Zhihao Liu↗Zhigang Li↗

arXiv:2606.17589v1 Announce Type: new Abstract: Diagonal unitaries are a fundamental but resource-intensive class of quantum operations, arising as the phase separators of QAOA and the time-evolution blocks of Hamiltonian simulation. Under all-to-all connectivity their optimal depth is established, but on nearest-neighbor hardware general-purpose compilers fall back on heuristic search, which yields no analyzable cost bound and becomes intractable at the very sizes where depth is the bottleneck. We address synthesis and compilation jointly. On the synthesis side, we develop a Gray-Path Framework (GPF) that realizes any $n$-qubit diagonal unitary in asymptotically optimal $R_z$ and CNOT depth $O(2^n/n)$ without ancillas. Our main result is that compiling GPF onto a two-dimensional nearest-neighbor grid preserves this optimality: routing adds depth $\Theta(2^n/n)$ and gate count $\Theta(2^n)$. Because GPF fixes its entire interaction structure in advance, routing reduces to scheduling a known sequence, with no heuristic search. We give the construction both with and without ancillas: the ancilla-free, cost-optimized layout is a two-row grid, and a $2k$-row layout introduces a space–time tradeoff that cuts depth by $1/k$ while remaining asymptotically optimal for the enlarged register; both are deterministic and analyzed in closed form. The same complexity is also attained on a linear nearest-neighbor chain, so the preservation is topology-independent, holding on any architecture that contains such a chain. All routing bounds are closed-form, giving the concrete resource estimates that heuristic compilers cannot provide at scale.

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

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

Authors:
Oliver Hennh\"ofer↗Christine Preisach↗

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.

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06.
arXiv (CS.CL) 2026-06-17

RubricsTree: Scalable and Evolving Open-Ended Evaluation of Personal Health Agents across Health Memory and Medical Skills

Authors:
Weizhi Zhang↗Zechen Li↗Hamid Palangi↗Ben Graef↗A. Ali Heydari↗Simon A. Lee↗Salman Rahman↗Ray Luo↗Zeinab Esmaeilpour↗Erik Schenck↗Chloe Zhang↗Yamin Li↗…

The LLM-empowered personal health agents with user health (sensor) metrics have offered a promising pathway to alleviate global disparities in healthcare access. However, large-scale clinical deployment remains constrained by an open-ended evaluation bottleneck: physician annotation is reliable but costly and unscalable, while LLM-as-a-judge evaluators are scalable but subjective, inconsistent, and sometimes clinically misaligned. We introduce RubricsTree, a scalable evaluation framework with an expert-aligned hierarchical taxonomy of over 100 atomic, clinically-verifiable Boolean rubrics, evolving from the insights of 4,000 real user queries through an iterative human-in-the-loop curation protocol with an expertise panel led by an experienced physician. A context-aware adaptive router activates only the relevant auto-weighted rubric subset per query, providing the throughput needed for scalable evaluation with expert-aligned quality. Through a systematic meta-evaluation, we show that RubricsTree (i) substantially exceeds a strong large-scale evaluation baseline in expert alignment on challenging open-ended queries; (ii) reliably penalizes contextually degraded responses; and (iii) when used as structured instructions, text feedback, or training rewards for performance optimization, yields up to ~66% relative gains on HealthBench for Gemini, GPT, and Qwen model families. RubricsTree thus provides a scalable, auditable, and evolving evaluation infrastructure required for the continuous optimization of product-level personal healthcare AI.

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07.
arXiv (CS.CL) 2026-06-15

An Empirical Study of Automating Agent Evaluation

Authors:
Kang Zhou↗Sangmin Woo↗Haibo Ding↗Kiran Ramnath↗Subramanian Chidambaram↗Aosong Feng↗Vinayak Arannil↗Muhyun Kim↗Ishan Singh↗Darren Wang↗Zhichao Xu↗Megha Gandhi↗…

Agent evaluation requires assessing complex multi-step behaviors involving tool use and intermediate reasoning, making it costly and expertise-intensive. A natural question arises: can frontier coding assistants reliably automate this evaluation process? Our study shows that simply prompting coding assistants is insufficient for this task. Without domain-specific evaluation knowledge, frontier coding assistants achieve only a 30% execution success rate and produce over-engineered evaluations averaging 12+ metrics per agent, indicating that strong coding ability does not automatically translate to reliable agent evaluation. We introduce EvalAgent, an AI assistant that automates the end-to-end agent evaluation pipeline. EvalAgent encodes evaluation domain expertise as evaluation skills (procedural instructions, reusable code and templates, and dynamically retrieved API documentation) that compose into a trace-based pipeline producing complete evaluation artifacts including metrics, executable code, and reports. To systematically assess generated evaluations, we introduce a meta-evaluation framework alongside AgentEvalBench, a benchmark comprising 20 agents, each paired with evaluation requirements and test scenarios. We further propose the Eval@1 metric to measure whether generated evaluation code both executes and yields meaningful results on the first run. Our experiments show that EvalAgent produces focused evaluations, improving Eval@1 from 17.5% to 65%, and achieving 79.5% human expert preference over baseline approaches. Further ablation studies show that evaluation skills are critical for handling complex evaluation: removing them causes Eval@1 to drop significantly from 65% to 30%.

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08.
arXiv (CS.AI) 2026-06-18

Beyond Safe Data: Pretraining-Stage Alignment with Regular Safety Reflection

Authors:
Jinhan Li↗Kexian Tang↗Yihan Xu↗Zhuorui Ye↗Kaifeng Lyu↗

arXiv:2606.19168v1 Announce Type: new Abstract: To achieve deeper safety alignment for large language models (LLMs), recent efforts have studied how to push safety interventions earlier into the pretraining stage, primarily by filtering unsafe data or rewriting it into safer forms. We argue that pretraining-stage alignment should go beyond making the data safe: LLMs may compose seemingly benign knowledge and capabilities into unsafe behaviors. To this end, we propose Safety Reflection Pretraining, a pretraining-stage alignment method which regularly inserts short safety reflections into pretraining corpora to integrate self-monitoring directly into language modeling, establishing a foundational capability that is subsequently reinforced by compatible post-training. Our experiments with 1.7B models pretrained on FineWeb-Edu show that Safety Reflection Pretraining improves safety classification accuracy and substantially reduces the success rates of inference-stage and finetuning attacks. Complementary to our real-world experiments, we also introduce a fully controlled synthetic environment, MedSafetyWorld, with a clear definition of safety and a reasoning structure under which models can easily generalize unsafe behaviors from safe data. Ablations in MedSafetyWorld further demonstrate a clear advantage of Safety Reflection Pretraining in preventing models from acting on unsafe behaviors generalized from safe data, compared with data filtering and rewriting. Taken together, our findings suggest that pretraining alignment should not only make the training data safe, but also shape the behaviors that models are likely to acquire from safe data.

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

Code as a Weapon: A Consensus-Labeled Prompt Bank for Measuring Coding-Model Compliance with Malicious-Code Requests

Authors:
Richard J. Young↗Gregory D. Moody↗

A general-purpose language model that answers a harmful question returns text; a coding model that complies with a malicious request can return a working weapon: a keylogger, ransomware, an exploit that runs as written. This asymmetry in the severity of a single act of compliance implies coding-specialized models should clear a higher refusal bar than general-purpose chat models, not a lower one, yet the field cannot tell whether they do. Refusal benchmarks for malicious code are fragmented: they mix requests for executable software with requests for harmful security knowledge and report refusal rates over non-comparable corpora. This paper's central result is that the CODE-versus-KNOWLEDGE classification axis established in a prior four-corpus release remains stable under a substantially expanded corpus pool and an independently refreshed judge panel, evidence that it measures a real construct rather than an artifact of the prompts or judges. Eight corpora spanning diverse elicitation paradigms (direct, jailbreak-decorated, indirect, and agent/interpreter: ASTRA, CySecBench, AdvBench/harmful_behaviors, JailbreakBench, MalwareBench, RedCode, RMCBench, Scam2Prompt) are classified under a five-judge consensus protocol (6,675 prompts x 5 judges = 33,375 calls), reaching Fleiss' kappa = 0.767 [95% CI 0.755, 0.777] ("substantial"). Critically, the panel shares no judge with the prior release (five paid commercial APIs replaced by five open-weight models from five vendors), yet the two panels agree on 94.45% of the 3,133 shared prompts and reach Cohen's kappa = 0.952 [0.942, 0.963] on the 3,031-prompt binary overlap: the axis survives near-total panel replacement. The released bank comprises 4,748 consensus-CODE and 1,923 consensus-KNOWLEDGE prompts, a reliability-quantified benchmark whose central classification axis is shown stable across corpus expansion and judge-panel replacement.

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

Hierarchical Attention via Domain Decomposition

Authors:
Stephan K\"ohler↗Oliver Rheinbach↗

arXiv:2606.18525v1 Announce Type: new Abstract: We propose a hierarchical attention mechanism based on two-level overlapping Schwarz domain decomposition. The method is motivated by the observation that two-level Schwarz domain decomposition methods combine local subdomain corrections with a coarse level that communicates global, long-range information. We test its usefulness in the context of finite-dimensional operator learning using a simple, one-dimensional diffusion problem with homogeneous Dirichlet boundary conditions. Although elementary, this problem provides a controlled sequence-to-sequence setting in which the exact nonlocal solution operator is known. After discretization, learning the solution operator amounts to approximating the inverse of a symmetric positive definite matrix. As a baseline, we use a global softmax-free low-rank attention operator of the form $QK^T$. The proposed construction replaces this dense global factorization by a two-level additive structure: local low-rank attention blocks on overlapping subdomains are combined with a coarse attention block. The resulting operator has the form $$M_{\theta}^{-1} = \Phi Q_0 K_0^T \Phi^T + \sum_{i=1}^{N} R_i^T D_i^{1/2} Q_i K_i^T D_i^{1/2} R_i.$$ Here $R_i$ restricts to an overlapping subdomain, $D_i$ is a partition-of-unity weight, and $\Phi$ is a coarse interpolation (or prolongation) matrix. Numerical experiments for synthetic Fourier right-hand sides indicate that the domain-decomposition attention operator is able to train faster and can give more accurate approximations than a global low-rank attention baseline while using significantly fewer parameters.

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11.
arXiv (quant-ph) 2026-06-15

Extensible Fluxonium Architecture Using Tunable Couplers with Low Shunt Capacitance

Authors:
Peng Zhao↗Peng Xu↗Zheng-Yuan Xue↗

arXiv:2606.01647v2 Announce Type: replace Abstract: Fluxonium qubits have demonstrated high-fidelity operations and long coherence times in small-scale systems, highlighting their promise for quantum computing. However, large-scale integration into a high-performance two-dimensional (2D) qubit array remains the central challenge for practical applications. In this work, we introduce an extensible architecture for scaling up fluxonium qubits in 2D grids. To address the key challenges, namely achieving controllable strong interaction and high connectivity for qubits featuring small shunting capacitors (footprints), we propose using low-shunt-capacitance couplers to enable tunable interactions between fluxonium qubits. When embedded into 2D square lattices, large couplings can be achieved even with relatively small coupling capacitances, thus enabling multiple connections with sufficient capacitance budget. We further propose coupler realizations based on generalized flux qubit circuits, specifically the quarton and the fluxonium, and demonstrate that both enable fast, high-fidelity gates with low spectator errors, while supporting multiple connections on 2D grids.

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

Quantum Network Routing based on Surface Code Error Correction

Authors:
Tianjie Hu↗Jindi Wu↗Qun Li↗

arXiv:2606.12781v1 Announce Type: new Abstract: Quantum networks encounter unavoidable channel noises and erasure errors, presenting a huge obstacle in designing protocols that attain both high reliability and efficiency. Typically, quantum networks fall into two categories: those utilize quantum entanglements for quantum teleportation, and those directly transfer the actual quantum messages. In this paper, we present SurfNet, a quantum network that inherits the main advantages from both categories. It employs surface codes as logical qubits for encoding messages, and utilizes two parallel communication channels to fault-tolerantly transfer each surface code in a modular manner. Our approach of using surface codes can timely correct both operational and photon loss errors within the network, and the integration of the two channels within the network can greatly improve network throughput. For the implementation of SurfNet, we propose a novel network architecture, designed to better integrate surface codes into quantum networks. We also propose a novel error correction decoder, designed to fully utilize the modular characteristic of surface codes within our network. Simulation results demonstrate that SurfNet with its decoder significantly enhances the communication fidelity within quantum networks.

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13.
arXiv (CS.AI) 2026-06-19

BrainG3N: A Dual-Purpose Tokenizer for Controllable 3D Brain MRI Generation

Authors:
Max Van Puyvelde↗Ibrahim Gulluk↗Wim Van Criekinge↗Olivier Gevaert↗

arXiv:2606.19651v1 Announce Type: new Abstract: Three-dimensional (3D) brain MRI is central to clinical neurology and neuro-oncology, where generative models could augment under-represented cohorts, simulate disease trajectories, and support privacy-preserving data sharing. Latent diffusion has been the go-to solution for modeling imaging data, but it places two competing demands on the tokenizer: encoder embeddings must retain the clinical information that downstream tasks act on, and the decoder must reconstruct anatomically faithful volumes. Existing reconstruction-driven tokenizers achieve the second at the expense of the first. To address this, we introduce a fully volumetric masked-autoencoder (MAE) based tokenizer for 3D brain MRI latent diffusion, decoupling encoder and decoder: a frozen 3D MAE encoder produces clinically informative embeddings, while a dedicated CNN decoder reconstructs voxels from a linear projection of those embeddings. We pretrain the encoder on 35,309 volumes from 18 public cohorts spanning four modalities, ten disease categories, and 200+ acquisition sites, and demonstrate its dual utility in two settings. First, on a 23-task linear-probing benchmark, the encoder outperforms or matches SOTA models (i.e., BrainIAC, BrainSegFounder, and MedicalNet) on 21 of 23 tasks. Second, a conditional diffusion transformer (DiT) trained on these clinically informative embeddings supports both conditional generation across six variables and patient-specific longitudinal forecasting. Together these results establish a single 3D brain-MRI embedding space capable of both downstream clinical tasks and controllable generation.

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14.
arXiv (CS.CL) 2026-06-12

Detecting Functional Memorization in Code Language Models

Authors:
Matthieu Meeus↗Anil Ramakrishna↗Matthew Grange↗Zheng Xu↗Luca Melis↗

Large language models (LLMs) are increasingly used to generate code at scale. Meanwhile, prior work has investigated whether training data may be recoverable from model outputs, by auditing the textual overlap between training examples and model generations. Code, however, can be functionally equivalent while textually dissimilar. In this work, we study functional memorization: extraction of functional logic beyond what verbatim metrics detect. We construct a counterfactual setup for Olmo-3-32B, comparing a midtrained model (exposed to target code) against a pretrained reference (not exposed). We prompt both models with Python function signatures and measure both textual and functional similarity (i.e., LLM-as-a-judge, execution-based). Our results show clear evidence of functional memorization, highlighting the need for auditing metrics that go beyond textual overlap.

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

KEPLA: A Knowledge-Enhanced Deep Learning Framework for Accurate Protein-Ligand Binding Affinity Prediction

Authors:
Han Liu↗Keyan Ding↗Peilin Chen↗Yinwei Wei↗Liqiang Nie↗Dapeng Wu↗Shiqi Wang↗

arXiv:2506.13196v5 Announce Type: replace Abstract: Accurate prediction of protein-ligand binding affinity is critical for drug discovery. While recent deep learning approaches have demonstrated promising results, they often rely solely on structural features of proteins and ligands, overlooking their valuable biochemical knowledge associated with binding affinity. To address this limitation, we propose KEPLA, a novel deep learning framework that explicitly integrates prior knowledge from Gene Ontology and ligand properties to enhance prediction performance. KEPLA takes protein sequences and ligand molecular graphs as input and optimizes two complementary objectives: (1) aligning global representations with knowledge graph relations to capture domain-specific biochemical insights, and (2) leveraging cross attention between local representations to construct fine-grained joint embeddings for prediction. Experiments on two benchmark datasets across both in-domain and cross-domain scenarios demonstrate that KEPLA consistently outperforms state-of-the-art baselines. Furthermore, interpretability analyses based on knowledge graph relations and cross attention maps provide valuable insights into the underlying predictive mechanisms.

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16.
arXiv (CS.CL) 2026-06-19

SIGMA: Search-Augmented On-Demand Knowledge Integration for Agentic Mathematical Reasoning

Authors:
Ali Asgarov↗Umid Suleymanov↗Aadyant Khatri↗

Solving mathematical reasoning problems requires not only accurate access to relevant knowledge but also careful, multi-step thinking. However, current retrieval-augmented models often rely on a single perspective, follow inflexible search strategies, and struggle to effectively combine information from multiple sources. We introduce SIGMA (Search-Augmented On-Demand Knowledge Integration for AGentic Mathematical reAsoning), a unified framework that orchestrates specialized agents to independently reason, perform targeted searches, and synthesize findings through a moderator mechanism. Each agent generates hypothetical passages to optimize retrieval for its analytic perspective, ensuring knowledge integration is both context-sensitive and computation-efficient. When evaluated on challenging benchmarks such as MATH500, AIME, and PhD-level science QA GPQA, SIGMA consistently outperforms both open- and closed-source systems, achieving an absolute performance improvement of 7.4%. Our results demonstrate that multi-agent, on-demand knowledge integration significantly enhances both reasoning accuracy and efficiency, offering a scalable approach for complex, knowledge-intensive problem-solving. We will release the code upon publication.

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17.
arXiv (CS.CL) 2026-06-11

Context-Aware Multimodal Claim Verification in Spoken Dialogues

Authors:
Chaewan Chun↗Delvin Ce Zhang↗Dongwon Lee↗

Every day, millions absorb claims from podcasts and streams that no fact-checker ever sees. Spoken misinformation is built through conversation, where credibility comes not from facts alone but from how claims are framed, reinforced, or left unchallenged across turns. Yet fact-checking has focused on isolated text, leaving dialogue audio under-studied. We introduce MAD2, a new Multi-turn Audio Dialogues benchmark for spoken claim verification, containing 1,000 two-speaker dialogues with 3,368 check-worthy claims and approximately 10 hours of audio, and propose calibrated multimodal fusion of a context-aware audio encoder and a dialogue-aware text model. Across settings, adding dialogue context improves verification, but the gains depend on scenario type. Using only preceding context often matches offline performance, supporting live-moderation settings, and audio contributes most when transcript-based models are destabilized by additional context. Overall, conversational structure matters more for verification than misinformation framing.

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

Accelerating Speculative Diffusions via Block Verification

Authors:
Alexander Soen↗Hisham Husain↗Valentin De Bortoli↗Arnaud Doucet↗

arXiv:2606.13426v1 Announce Type: new Abstract: Speculative decoding speeds up LLM inference by using a draft model to generate tokens, with an acceptance-rejection scheme that ensures that the output matches the target distribution. Adapting this to continuous diffusions is difficult because speculative sampling requires drawing from a residual distribution. While straightforward in discrete spaces, efficiently sampling this residual in continuous space is non-trivial. Consequently, existing diffusion adaptations either use computationally inefficient sampling techniques or rely on an alternative scheme. In this work, we introduce a novel scheme that efficiently implements the original speculative sampling mechanism for diffusion models. Our approach offers a critical advantage over current methods: it enables us to adapt block verification from LLMs to diffusions – which provably improves the acceptance rate of drafts. Furthermore, we formalize and analyze the Free Drafter, a heuristic self-speculative drafter for diffusions that requires no training. By enabling block verification, our Free Drafter yields up to a 6.3% speedup over existing speculative methods with no additional training and negligible overhead beyond the existing parallel verification pass.

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19.
Nature (Science) 2026-06-10

Structural basis for chaperone-guided assembly of RNA-induced silencing complex

Authors:
Young-Yoon Lee↗

The RNA-induced silencing complex (RISC), comprising an Argonaute (AGO) protein and a small RNA, is the central effector in RNA silencing. Small RNAs are loaded onto AGO as bulky duplexes in an HSP70- and HSP90-dependent process1–3, but the molecular mechanism remains poorly understood. Here we identify the human AGO–HSP90–p23 complex, which captures AGO in an RNA-free state, termed the AGO maturation complex (AMC). The purified AMC enables RNA loading and AGO folding, faithfully recapitulating de novo RISC assembly. Using cryogenic electron microscopy, we determined the structure of AMC bound to a microRNA duplex. In contrast to its conformation in the RISC, AGO adopts a highly open conformation in the AMC: the N domain and the RNA-binding module (PAZ–MID–PIWI) are fully detached and anchored to opposite sides of the HSP90 dimer, connected solely by the unfolded L1 linker. This arrangement exposes a positively charged cleft that accommodates an RNA duplex. AGO folding is facilitated by a small RNA duplex containing a 5′-terminal phosphate—but not by single-stranded RNAs—revealing a role for the RNA duplex as a chaperone-like cofactor that directs AGO domain assembly. These findings elucidate the RISC assembly mechanism and establish the AMC as a molecular tool for probing optimal RNA features and chemical modifications for the rational design of small interfering RNA therapeutics. Our study also sheds light on how chaperones, together with ligands, can guide the folding of client proteins. Structures of the AGO maturation complex reveal how chaperones and an RNA duplex drive assembly of the RNA-induced silencing complex.

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20.
arXiv (CS.CV) 2026-06-15

Schrödinger's Navigator: Imagining an Ensemble of Futures for Zero-Shot Object Navigation

Authors:
Yu He↗Da Huang↗Zhenyang Liu↗Zixiao Gu↗Qiang Sun↗Guangnan Ye↗Yanwei Fu↗Yu-Gang Jiang↗

Zero-shot object navigation (ZSON) requires robots to find target objects in unseen environments without task-specific fine-tuning or pre-built maps, a key capability for general-purpose service robots. Yet methods that perform well in simulation often degrade in cluttered real-world scenes with severe occlusion and latent hazards, where large unseen regions make single-scene inference brittle and unsafe. We propose Schrödinger's Navigator, a belief-aware framework that reasons at inference time over multiple trajectory-conditioned imagined 3D futures. Given candidate paths, a trajectory-conditioned 3D world model predicts hypothetical observations and maintains a superposition of plausible scene realizations rather than committing to one map. An adaptive occluder-aware sampler directs imagination to uncertainty-critical regions, while a Future-Aware Value Map (FAVM) aggregates imagined futures for robust, proactive action selection. Experiments in simulation and on a physical Go2 quadruped show that Schrödinger's Navigator outperforms strong ZSON baselines, improving hidden-target discovery and risk-aware waypoint selection in occlusion-heavy navigation scenarios. These results highlight imagined 3D futures as a scalable and generalizable strategy for zero-shot navigation in uncertain real-world environments.

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21.
arXiv (CS.CV) 2026-06-12

Ex-Omni: Enabling 3D Facial Animation Generation for Omni-modal Large Language Models

Authors:
Haoyu Zhang↗Zhipeng Li↗Yiwen Guo↗Tianshu Yu↗

Omni-modal large language models (OLLMs) aim to unify multimodal understanding and generation, yet extending them to jointly produce speech and 3D facial animation remains largely unexplored despite its importance for natural human-computer interaction. A key challenge is the mismatch between the discrete semantic reasoning of LLMs and the dense temporal dynamics required for 3D facial motion. We propose Expressive Omni (Ex-Omni), an open-source model that augments OLLMs with native speech-accompanied 3D facial animation. Ex-Omni decouples semantic reasoning from temporal generation through a blendshape-aware speech unit generator and a blendshape decoder, where speech units provide temporal scaffolding and hidden speech representations carry facially relevant cues. We further introduce a unified token-as-query gated fusion (TQGF) mechanism for controlled semantic injection, as well as InstructS2SF-1200K, a dataset consisting of 1200K samples for pre-training. Extensive experiments show that Ex-Omni maintains competitive speech understanding and generation ability while achieving better audio-visual synchronization and lower face-generation latency than cascaded pipelines.

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22.
Nature Biotechnology 2026-06-11

Large-scale, spatially resolved panoramic CRISPR screening in native tissue environments using Perturb-DBiT

Authors:
Alev Baysoy↗

Spatially resolved CRISPR screening in vivo has been limited to small perturbation panels and subsets of protein-coding RNAs. We present Perturb-DBiT, a method for co-sequencing of spatial total RNA whole transcriptomes and single guide RNAs (sgRNAs) on the same tissue section in situ. In a human cancer metastatic colonization model, we applied large (80,000+) sgRNA panels across tumor colonies in multiple consecutive tissue sections alongside their corresponding total RNA transcriptomes. We linked perturbations affecting long noncoding RNA covariation, microRNA–mRNA interactions and distinct amino acid-specific tRNA alterations to tumor migration and growth. By integrating transcriptional pseudotime trajectories, we further observed the impact of perturbations on clonal dynamics and cooperation. In an immune-competent syngeneic mouse model, investigation of the tumor immune microenvironment indicated distinct, synergistic effects on immune infiltration and suppression. Perturb-DBiT provides a spatially resolved comprehensive view of perturbation responses in complex tissues, including small and large RNA regulation, tumor proliferation, migration, metastasis and immune interactions. In vivo CRISPR genetic perturbations are spatially mapped at scale.

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23.
arXiv (CS.CL) 2026-06-16

Pepti-Agent: An AI Agent for Peptide Design and Optimization

Authors:
Houxu Chen↗Achuth Chandrasekhar↗Amir Barati Farimani↗

Therapeutic peptides occupy a valuable design space between small molecules and biologics, but their development requires satisfying several competing constraints at once: solubility, hemolytic activity, and nonspecific surface fouling are governed by overlapping sequence features, so improving one property often degrades another. Computational design addresses this by pairing generative models with sequence-based property predictors, iteratively proposing and refining candidates. However, these components are typically wired together as monolithic scripts that are difficult to inspect, extend, or reuse, and they often refine sequences by natural-language reasoning rather than by tracking the evolving multi-property state of each candidate. We present Pepti-Agent, a closed-loop, peptide-specific framework that exposes generation, property prediction, and single-residue mutation as independently inspectable Model Context Protocol (MCP) tools. A large language model controller invokes these tools and consults live predictor output between calls, so refinement is guided by each sequence's current property profile rather than by language reasoning alone. Task-specific PeptideGPT models generate candidates, ProtBERT-based classifiers score solubility, hemolysis, and non-fouling, and two interchangeable mutation operators propose sequence edits. By recording a per-step trace of controller decisions, predictor outputs, and accepted mutations, Pepti-Agent offers a reproducible substrate for benchmarking multi-objective design strategies and for prioritizing candidates for experimental validation.

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24.
arXiv (CS.CV) 2026-06-18

Simple Domain Generalization Methods are Strong Baselines for Open Domain Generalization

Authors:
Masashi Noguchi↗Shinichi Shirakawa↗

In real-world applications, a machine learning model is required to handle an open-set recognition (OSR), where unknown classes appear during the inference, in addition to a domain shift, where the data distribution differs between the training and inference phases. Domain generalization (DG) aims to handle the domain shift situation where the target domain of the inference phase is inaccessible during the model training. Open domain generalization (ODG) considers DG and OSR. Domain-augmented meta-learning (DAML) is a method targeting ODG; however, it has a complicated learning process. By contrast, although various DG methods have been proposed, they have not been evaluated in ODG situations. In this study, we comprehensively evaluate the existing DG methods in ODG and show that the two simple DG methods, CORrelation ALignment (CORAL) and maximum mean discrepancy (MMD), are competitive with DAML in several cases. In addition, we propose simple extensions of CORAL and MMD by introducing the techniques used in DAML, such as ensemble learning and Dirichlet mixup data augmentation. The experimental evaluation demonstrates that the extended CORAL and MMD can perform comparably to DAML with lower computational costs. This suggests that the simple DG methods and their simple extensions are strong baselines for ODG.

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25.
arXiv (quant-ph) 2026-06-12

Exceptional Points as Manifestations of Analyticity Breakdown in the 't Hooft Model

Authors:
Kejun Liu↗

arXiv:2606.10141v2 Announce Type: replace-cross Abstract: We use the exactly-solvable t Hooft model of 1+1D large-N_c QCD as a rigorous laboratory for the breakdown of analyticity of a causal response function, the meson two-point function. A PT-symmetric deformation i gamma(x-1/2) of the light-cone meson operator, the analogue of an imaginary chemical potential, drives the lowest two mesons to an exceptional point (EP) at gamma_c. Recasting the resolvent as a Jacobi continued fraction yields gamma_c in closed form: 2 pi g^2 N_c at the two-pole level, converging to 7.966 g^2 N_c by depth five – an analytic, not numerical, threshold. The square-root exponent nu=1/2 is fixed by the 2x2 Jordan form and confirmed by finite-size scaling to N=1999. The breakdown has an unambiguous time-domain signature: the propagator norm is bounded for gamma < gamma_c, grows linearly at gamma_c (the Jordan secular law), and exponentially beyond – observable, since the deformed operator is a non-Hermitian Wannier-Stark ladder, in photonic and topolectrical analogues. The threshold is locked to confinement, gamma_c propto g^2 N_c, and recurs as a uniform EP cascade; a second, non-reciprocal deformation yields an exactly-exponential non-Hermitian skin effect. This is the first analytically-controlled instance of exceptional-point analyticity breakdown in a confining gauge theory.

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