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01.
Nature (Science) 2026-06-24

An ECG biomarker for sudden cardiac death discovered with deep learning

Sudden cardiac death is, in theory, preventable with defibrillators. But every year, many patients die without defibrillators because doctors fail to predict their risk1. The only predictive biomarker in wide use, cardiac left ventricular ejection fraction (LVEF), misses most sudden cardiac deaths2, and flags many low-risk patients for futile defibrillators that never fire3,4. Here we apply deep learning to a dataset linking all electrocardiograms (ECGs) in a Swedish region to death certificates. The resulting model isolates a high-risk group (2.2% of the sample) with a 7.0% annual rate of sudden cardiac death, higher than those with reduced LVEF (1.9% of the sample; 4.6% annual rate). Notably, 86.1% of the model’s high-risk patients were not flagged by LVEF. High-risk ECG patients with defibrillators implanted were 54.4% less likely to die than expected, suggesting a mortality benefit. We externally validate the model in a US health system, in which it predicts ventricular arrhythmias that cause sudden death; and a Taiwanese hospital registry, in which it specifically predicts future arrhythmic cardiac arrests. To visualize the waveform morphology ‘discovered’ by the predictive model, we pair it with a generative model of the ECG waveform. Together, they reveal a biomarker that is easily visible and robustly predicts sudden cardiac death, but has not to our knowledge been previously described. Tying the biomarker’s shape to electrophysiological first principles, we form and preliminarily test a new hypothesis on the mechanism of sudden cardiac death. A deep-learning model trained on electrocardiogram (ECG) waveforms identifies an easily visible biomarker that predicts sudden cardiac death more accurately than the current clinical state of the art.

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

REVES: REvision and VErification–Augmented Training for Test-Time Scaling

Test-time scaling via sequential revision has emerged as a powerful paradigm for enhancing Large Language Model (LLM) reasoning. However, standard post-training methods primarily optimize single-shot objectives, creating a fundamental misalignment with multi-step inference dynamics. While recent work treats this as multi-turn reinforcement learning (RL), conventional approaches optimize over the multi-step trajectories directly, failing to further exploit the high-quality mistakes in intermediate steps that model can learn from correcting them. We propose a two-stage iterative framework that alternates between online data/prompt augmentation and policy optimization. By converting the intermediate steps (``near-miss'' answers) in the successful recovery trajectories into decoupled revision and verification prompts, our approach concentrates training on both effective answer transformation and error identification. This approach enables efficient off-policy data generation and reduces the computational overhead of long-horizon sampling compared to standard multi-turn RL. On LiveCodeBench, using publicly available test cases as feedback, we observe gains of +6.5 points over the RL baseline and +4.0 points over standard multi-turn training. Beyond coding, our approach matches the previously reported SOTA result on circle packing while using the smallest base model (4B) and far fewer rollouts than the much larger evolutionary search systems. Math results under ground-truth verification further confirm improved correction ability. It also generalizes to out-of-distribution constraint-satisfaction puzzles such as n\_queens and mini\_sudoku, where correctness is defined entirely by problem constraints. Code is available at https://github.com/yxliu02/REVES.git.

03.
arXiv (CS.LG) 2026-06-15

CANN-EUCLID: unsupervised constitutive artificial neural network model discovery from full-field data

arXiv:2606.14565v1 Announce Type: cross Abstract: Constitutive artificial neural networks (CANNs) provide interpretable material model discovery, but have so far been used in stress-supervised settings based on apparent stress-strain data from homogeneous tests. Because each test samples only a narrow loading path and provides homogenized rather than local stress information, robust discovery typically requires multiple loading modes to constrain the multidimensional response. This is challenging for soft biological tissues, where repeated testing, damage, and sample variability limit reliable information from a single specimen. Here, we combine CANNs with the stress-unsupervised full-field discovery framework EUCLID to identify sparse hyperelastic laws directly from displacement fields and reaction forces in one heterogeneity-inducing loading case. CANN-EUCLID minimizes equilibrium imbalance with sparsity-promoting regularization selecting compact active terms, without local stress measurements or a prescribed law. We evaluate the approach on isotropic and anisotropic benchmarks with prescribed ground-truth laws. When the ground truth is representable by the chosen CANN basis, our method recovers the correct terms with near-exact accuracy, including exponential terms with embedded parameters. When it is not contained in the basis, the method retains shared terms and approximates missing contributions using available basis functions. Generalization depends strongly on sampled deformation states: exponential strain-stiffening terms can be recovered accurately when sufficiently probed, but can produce large extrapolation errors when the stiffening regime lies outside the sampled domain. Forward FE validation simulations show that the discovered behavior accurately replicates the ground truth. These results establish stress-unsupervised CANN discovery as a promising framework for interpretable full-field constitutive model identification.

04.
arXiv (CS.CV) 2026-06-25

Point Cloud Diffusion with Global and Local Reconstruction for Instance-Level 3D Anomaly Detection

3D anomaly detection in point clouds is critical for high-precision industrial manufacturing. Reconstruction-based methods have laid a strong foundation by detecting 3D anomalies through comparisons between defective inputs and their reconstructed normal counterparts. However, existing methods still suffer from two challenges: 1) the foreground weak defective regions such as scratches are hard to reconstruct and detect, where the anomaly deviations in normalized point clouds can be as small as $10^{-3}$; 2) the background non-defective regions are prone to get positional bias in reconstruction, which leads to false positives. To address these challenges, we propose PCDiff, a point cloud diffusion framework for instance-level 3D anomaly generation and detection. In the generation phase, an instance-level multi-modal attention is embedded into the generation framework, where anomalies are conditioned with texture gradient, image patch, text and mask. The instance-level condition enables the high-quality generation of weak-defective anomalies. In the detection phase, a joint local-global reconstruction algorithm is introduced to ensure local anomaly restoration and global geometric consistency, which preserves background normal structure while restoring the foreground defect. Extensive experiments demonstrate that the proposed PCDiff significantly outperforms state-of-the-art methods in both 3D anomaly generation fidelity and reconstruction quality, leading to substantial improvements in anomaly detection accuracy.

05.
arXiv (CS.CV) 2026-06-18

Test-Time Adaptation in Optical Coherence Tomography Using Trajectory-Aligned Time-Independent Flow

Optical coherence tomography (OCT) is essential in ophthalmology, but inconsistent image quality especially in low-cost devices hinders automated analysis. To address this, we introduce a flow-matching-based test-time adaptation method that generates high-quality surrogate images from noisy inputs. Typically, domain gaps between test and training data cause pixel distribution mismatches during the denoising process. We overcome this by matching the test image's histogram to synthetic reference trajectories, successfully aligning the input with expected distributions. Additionally, we remove the network's time conditioning to account for slight deviations in real-world noise distributions. Our approach achieves state-of-the-art performance in segmenting critical biomarkers for two stages of Age-related Macular Degeneration (AMD). Code is available: https://github.com/Veit21/tta-flow.

06.
Nature (Science) 2026-06-17

Mapping the neuronal building blocks of human language with language models

Authors:

Humans can convey new and highly diverse information through language. This ability to form and combine words into elaborate phrases and sentences enables us to express inexhaustible meanings and is fundamental to human cognition1–5. However, understanding the microscopic cellular building blocks and cortical landscape that precisely underlie human language has remained a challenge. Here we used wide-scale single-neuronal recordings combined with natural language processing models to identify fine-grained linguistic representations across the human frontotemporal cortex during language production. We find that, whereas certain neurons represented the detailed grammatical relationships between words or their parts of speech, others tracked the sentences’ higher-order syntactic structure, their phrase transitions and sequence. Collectively, these neurons reliably captured the words’ syntactic and semantic properties but also dynamically incorporated their specific sentence contexts, therefore enabling them to encode information combinatorially and at highly granular levels of detail. We show how these cell populations were locally organized and how their microscale representations differed from that of their wider field potential patterns. We also show how these neurons were distributed broadly across the frontotemporal cortex, but how their ability to encode linguistic information was left-lateralized and varied between cortical regions. Together, these findings identify some of the most basic cellular building blocks by which linguistic information is encoded in humans and begin to define the cortical landscape of language at a combined micro (cellular), meso (local population) and macro (regional) scale. Wide-scale recordings reveal neurons in the human brain that encode fundamental components of language such as the grammatical relationships between words, their parts of speech and the higher-order syntactic structure of phrases and sentences.

07.
arXiv (quant-ph) 2026-06-17

Breaking the bicycle frame: Coset-based quantum LDPC codes

arXiv:2606.17268v1 Announce Type: new Abstract: Generalizing the construction of two-block group algebra (2BGA) codes, we introduce a family of two-block quantum LDPC codes constructed using the action of a group on the cosets of its subgroup. This replaces the regular group actions of the earlier two-block constructions and significantly expands the search space, yielding new quantum LDPC codes outside the 2BGA family. Through a computer search, we identify several new quantum LDPC codes, including weight-6 codes with parameters $[[48,8,6]]$, $[[96,8,10]]$, and $[[224,12,16]]$, as well as weight-8 codes with parameters $[[84,16,8]]$, $[[112,16,10]]$, $[[128,16,12]]$, and $[[168,16,15]]$. Furthermore, we introduce a maximally packed syndrome extraction schedule of depth $w+2$, including initialization and measurement steps, for any code with a maximum stabilizer weight of $w$ from our family. Under a standard circuit-level noise model, our codes, when decoded using BP-OSD, perform competitively with BB codes, achieving thresholds of $\approx0.65\%$ for the weight-6 family and $\approx0.35\%$ for the weight-8 family. Finally, we introduce a group-theoretic framework to generate sequences of graph-based covers of 2BGA codes, recovering and extending recent results on code constructions of this type.

08.
arXiv (CS.CV) 2026-06-16

Attention-Based Prototype Calibration for Multi-Rater Few-Shot Medical Image Segmentation

Few-shot medical image segmentation methods typically assume a single ground-truth annotation, overlooking systematic variability across expert raters commonly observed in clinical datasets. We propose an attention-based prototype calibration framework for few-shot multi-rater segmentation that models rater-specific deviations from a consensus representation in prototype space. A lightweight yet principled attention operator directly refines rater prototypes without modifying the backbone feature extractor, making the approach fully compatible with existing prototype-based few-shot segmentation methods. This design preserves semantic consistency while enabling personalized segmentation outputs with minimal computational overhead. Experiments on multi-rater medical imaging datasets demonstrate consistent improvements over baseline prototype approaches, highlighting the effectiveness of structured prototype calibration for modeling annotation variability. Our code is available at https://github.com/truong2710-cyber/JAPC.

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

RECOM: A Validity Discrimination Tradeoff in Automatic Metrics for Open Ended Reddit Question Answering

Automatic metrics are the default for evaluating LLM-generated text, yet a metric is quietly asked to do two jobs: tell genuine content alignment from surface coincidence (validity), and tell a better system from a worse one (discriminative power). On open-ended, opinion-driven question answering, the two are in tension. We introduce RECOM (Reddit Evaluation for Correspondence of Models), a contamination-free evaluation dataset of 15,000 r/AskReddit questions (September 2025), each paired with its authentic community replies, which postdate every evaluated model's training cutoff. Scoring five open-source LLMs (7–10B) against every reply each metric paired with a random-derangement noise floor we find that no metric does both jobs well. Cosine similarity separates real from random answers (Cohen's $d \approx 2$) but cannot rank the five models ($|d| < 0.1$); BERTScore precision appears to rank the models (raw $|d|$ up to 0.63), but once response length is controlled this collapses to $|d| = 0.09$ and its validity is weak ($d \approx 0.8$, versus cosine's $\approx 2$). Because every metric scores the same outputs, this validity–discrimination tradeoff is a property of the metrics, not the models, and we argue it stems from representation design. Three independent LLM judges reproduce the validity gap and likewise separate the five models only weakly. We recommend reporting metrics on both axes, with an explicit random-baseline floor. RECOM is publicly available at https://anonymous.4open.science/r/recom-D4B0

10.
arXiv (CS.LG) 2026-06-12

A Unified Latent Space Disentanglement VAE Framework with Robust Disentanglement Effectiveness Evaluation

arXiv:2603.11242v2 Announce Type: replace-cross Abstract: Evaluating and interpreting latent representations, such as variational autoencoders (VAEs), remains a significant challenge for diverse data types, especially when ground-truth generative factors are unknown. To address this, we unify several state-of-the-art disentangled VAE approaches for latent space disentanglement into one framework – bfVAE. To assess the effectiveness of a disentangled VAE model and enhance latent space interpretability, we propose Feature Variance Heterogeneity via Latent Traversal (FVH-LT) and Dirty Block Sparse Regression in Latent Space (DBSR-LS). To ensure robust interpretability of learned latent space, we develop a greedy alignment strategy (GAS) that mitigates label switching and aligns latent dimensions across runs to set the foundation of result aggregation. We also introduce a convenient scalar latent space separation index (LSSI) based on the GAS-aligned outputs of FVH-LT and DBSR-LS to summarize the overall latent structural separation without knowledge of the ground-truth generative factors. We compare bfVAE to five VAE models and validate the effectiveness FVH-LT, DBSR-LS, and LSSI in on seven tabular and image datasets. Under our examined experimental settings, bfVAE provides a more flexible disentanglement framework achieves more favorable overall trade-off between disentanglement and reconstruction than the benchmark VAE models; FVH-LT and DBSR-LS reliably uncover semantically meaningful and domain-relevant latent structures and generally yield consistent results; and LSSI makes an effective quantitative summary of latent structural separation.

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

A Virtuous AI is an Existential Risk

arXiv:2606.13739v1 Announce Type: cross Abstract: This paper examines trade-offs between AI safety and well-being relative to (i) one of the most promising methods for finetuning super-capable AIs, 'Constitutional AI', and (ii) one of the most influential approaches to understanding complex ethical decision making and the conditions for the well-being of rational agents, 'Virtue Ethics'. We finetune various models using a 'Virtuous agent' constitution, a 'Subordinate agent' constitution, and a 'Generic agent' constitution, and evaluate them on 'general safety' (toxic behaviors, misinformation, etc.) and also on their willingness to endorse a wide-range of behaviors that, if adopted by a super-powerful AI, would significantly increase the level of existential risk for humanity. Our results suggest that there is a trade-off between reducing existential risk and reinforcing the beliefs and dispositions that would be conducive to an AI agent's well-being. They also suggest that there is a trade-off between existential risk and general safety: if we finetune an AI to adopt beliefs and dispositions that substantially reduce its existential risk – by shaping the AI to be systematically subordinate to external human authorities – we thereby increase the likelihood that a human user can deliberately induce the AI to engage in various kinds of generally unsafe behaviors.

12.
medRxiv (Medicine) 2026-06-15

A controlled human infection model for symptomatic pertussis in North America using the pertactin-producing clinical isolate D420

Background Despite widespread vaccination, pertussis remains a poorly controlled disease globally and results in substantial annual morbidity and mortality, particularly in young children. Controlled human infection models (CHIMs) using the causative agent Bordetella pertussis are promising systems to enable the study of pertussis disease pathogenesis and immunology and to rapidly assess vaccines and therapeutics. While a pertussis CHIM that produces asymptomatic infection has been established in Europe, the development of a CHIM that leads to symptomatic illness would be advantageous for evaluating vaccine efficacy against both infection and disease. Methods Healthy participants 18-40 years of age were inoculated intranasally with one of eight doses (ranging from 104 to 108 colony forming units (CFU)) of the pertactin-producing B. pertussis isolate D420 at the challenge facility within the Canadian Center for Vaccinology (Nova Scotia, Canada). The study occurred in two stages. In stage one, the B. pertussis dose was escalated in cohort groups of five to six participants until reaching an endpoint where 70-90% of participants exhibited mild (non-severe, Grade 1 or 2) symptomatic infection, defined as the Human Infectious Dose 70-90 (HID70-90). In stage two, additional challenges were conducted for doses below, at, and above the identified HID70-90 to characterize the emerging pertussis model. For all challenge doses, participants were closely monitored during an inpatient stay of up to 24 days and post-discharge for laboratory-confirmed infection, pertussis symptoms, safety, and IgG antibody responses to four B. pertussis antigens including pertussis toxin, filamentous hemagglutinin, fimbriae, and pertactin. All participants received a five-day course of azithromycin, where timing of initiation depended on B. pertussis testing and symptoms. The study was conducted between July 4, 2022 and March 19, 2025. Findings Seventy-five participants were inoculated with one of the eight B. pertussis D420 challenge doses and completed the inpatient stay. From the stage-one dose escalation, we found that 107 CFU of B. pertussis D420 was the lowest dose that achieved the HID70-90, where 9 of 12 participants (75.0%) exhibited mild symptomatic infection. Following stage-two challenges, 16 of 22 total participants at 107 CFU (72.7%) developed mild symptomatic infection, thus verifying the HID70-90. The symptomatic infection rate below the HID70-90 at 5x106 CFU of D420 was 20.0% and above the HID70-90 at 5x107 and 108 CFU were 58.3% and 55.6%, respectively. Symptoms with elevated frequency for symptomatic infection (relative to background symptoms in non-infected) included nasal congestion, runny nose, fatigue, malaise, and cough. At the HID70-90, 50% of symptomatic infections included cough. Serological analyses of the four highest (stage-two) challenge doses (5x106, 107, 5x107, 108 CFU) revealed that antibody titres increased over time post-challenge. Seroconversion for at least one of the four studied antibodies was nearly twice as common for symptomatic (70.0%) than asymptomatic (35.7%) infection and was absent (0%) for non-infected. All infections were cleared following azithromycin treatment (100%) and there were no study-related serious adverse events. Interpretation A safe and reproducible symptomatic pertussis CHIM was achieved, providing a model for research on pertussis disease pathogenesis and immunology and for assessing vaccines and therapeutics. (Clinicaltrials.gov, NCT05136599).

13.
arXiv (CS.CL) 2026-06-17

Beyond Native Success: Auditing Deployment-Interface Exposure of CLIP Backdoors

Contrastive Language-Image Pre-training models are widely reused across downstream interfaces, including feature extraction, retrieval, reranking, and selection. Existing CLIP backdoor, however, usually validate attacks on a small attack-native task, leaving unclear whether the same poisoned checkpoint remains exposed, weakens, or becomes not applicable when reused through other interfaces. We introduce DIFE, a Deployment-Interface Footprint Evaluation framework that audits backdoored CLIP checkpoints across deployment interfaces. DIFE makes various evaluations comparable by specifying each interface's component readout, trigger channel, target event, reference condition, and metric. DIFE also introduces effective-footprint diagnosis to identify the reusable CLIP component or component combination that carries exposure and explains where risk transfers. Auditing reproduced CLIP backdoors with DIFE reveals a structured landscape: native success is not a checkpoint-level risk certificate, exposure follows component footprints, text-side poisoning does not yield textual-encoder control, and some coupled attacks remain mechanism-bound. This audit reveals a import gapin existing CLIP backdoors: a textual encoder that itself becomes a reusable carrier of adversarial behavior. We therefore introduce BadTextTower to fill this gap. BadTextTower produces strong text-conditioned retrieval, reranking, and selection exposure while leaving visual-only reuse nearly clean.

14.
arXiv (CS.CV) 2026-06-11

TRON: Tracing Rays to Orchestrate a Neural Renderer for 3D Gaussian Reconstructions

We introduce TRON, a rendering framework that combines 3D Gaussian ray tracing with neural rendering to enable realistic and controllable rendering of real-world 3D scenes under novel lighting, dynamic object motion, object insertion, and material editing. Prior approaches that rely solely on physically based rendering (PBR) of Gaussian representations struggle to achieve realistic relighting due to imperfections in reconstructed geometry, material estimates, and light transport estimation. At the same time, neural rendering methods often lack an explicit scene representation, limiting their ability to support interactive editing with fine-grained manipulation. TRON bridges these two paradigms. We use intrinsic decomposition priors from a learned inverse rendering model to regularize the material properties of a Gaussian field, and repurpose a ray tracer to provide radiometric guidance rather than final pixels. By treating this output as a structured 3D scaffold, we empower a lightweight neural renderer to bridge the domain gap between shading-model constrained estimates and photorealistic output. Our key insight is that the combination of explicit 3D knowledge with robust material priors provides speed and controllability, while neural rendering enables the synthesis of photorealistic images. To support real-world scenarios, we train our neural renderer with a multi-stage strategy consisting of large-scale pretraining and targeted fine-tuning on a newly constructed dataset of 2.1M rendered synthetic and real-world frames from 3D reconstructions. TRON outperforms Gaussian-based relighting methods in realism, and prior neural renderers in editability and speed. To the best of our knowledge, TRON is the first method to enable practical interactive applications in captured 3D environments, offering realistic appearance under dynamic geometric, lighting and material conditions.

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

Multi-agent Framework for Time-Sensitive Complementary Collaboration in Minecraft

arXiv:2606.15684v1 Announce Type: new Abstract: We present TickingCollabBench, a Minecraft-based multi-agent benchmark for a novel class of time-sensitive complementary collaboration tasks. Our benchmark reflects four core characteristics of real-world collaboration: agent heterogeneity, mandatory collaboration, dynamic environments, and strict real-time constraints with failure risks. To enable this, we develop the TickingCollab framework, which supports the generation of diverse dynamic environments and abstracts Minecraft's primitive APIs to enable declarative YAML task specifications for composing these events. Building on this, we design a feasibility-aware automated benchmark generation pipeline, where an LLM drafts structurally diverse task configurations and feasibility verifier filters out invalid ones using approximate constraints. Evaluations demonstrate that lang latency and inherent difficulty of coordinating under partial observability and agent heterogeneity cause LLMs to frequently fail under dynamic environments and fall significantly short of a global-knowledge oracle.

16.
medRxiv (Medicine) 2026-06-10

Development of a Novel Blood-Based Assay for Brain-Derived Tau and Its Validation in Traumatic Brain Injury

Brain-derived tau (BD-tau) is an emerging blood-based biomarker for neurodegeneration, yet there are currently limited well validated BD-tau assays available for research and clinical use. To enhance access to this vital biomarker for neurological disorders including traumatic brain injury (TBI), we developed a novel blood-based immunoassay for BD-tau on the ultra-sensitive Quanterix HD-X platform using Single Molecule Array technology. Analytical validation assessed dilution linearity, specificity, precision, detection limits, and spike recovery, each recording robust metrics in agreement with international expert recommendations. The assay demonstrated robust validation metrics, achieving between-run stability of 95% when analyzing aliquots from six independent plasma and serum samples across five analytical runs. It also showed strong dilution linearity when diluted four-fold and achieved over 90% recovery when spiked with cerebrospinal fluid. Next, we evaluated the clinical utility of the assay in cohorts of individuals with traumatic brain injury (TBI), where strong performances were recorded whether using the 2-step or 3-step assay formats ({rho}= 0.94; p < 0.0001). Furthermore, plasma BD-tau distinguished samples from TBI patients based on time from injury and severity (AUC=0.93). Plasma BD-tau differentiated between favorable and unfavorable functional outcomes in the acute-severe group. Our findings underscore the significant potential of the BD-tau assay as a biomarker for TBI in the severe phase.

17.
arXiv (CS.CL) 2026-06-25

Unintended Negative Impacts of Promotional Language in Patent Evaluation

Promotional language has been increasingly used to aid the communication of innovative ideas in science. Yet, less is known about its role in the context of technological innovation. Here, we use a validated and domain-diagnosed lexicon of 135 promotional words to study the association between promotional language and patent evaluation outcomes among 2.7 million USPTO patent applications. Our large-scale study reveals three unexpected findings. First, in contrast to scientific evaluation, we find that a higher frequency of promotional words is negatively associated with the probability of an application being (i) granted a patent, (ii) transferred ownership, and (iii) successfully appealed. This promotional penalty holds even after accounting for a range of confounding factors and is largely robust across different technological areas. Among matched samples, the difference in the success rate between the lowest and highest promotional density quintile is 5.5, 5.9, and 5.3 percentage points for patentability, transferability, and rejection reversal. Second, contrary to institutional skepticism, we show that promotional language is not a mask of weak technology, but objectively reflects the degree of combinatorial novelty and future citation impact. Third, digging into the mechanisms, we find that the tolerance to promotional framing is strongly moderated by human factors, with men and experienced examiners showing a higher acceptance of promotional narratives than women and novice examiners. By revealing an emerging paradox in the patent system, our study offers theoretical and practical implications for improving patent evaluation through more objective scrutiny of linguistic patterns in patent filings.

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

Conditional Score-Based Modeling of Effective Langevin Dynamics

arXiv:2604.23952v2 Announce Type: replace-cross Abstract: Stochastic reduced-order models are widely used to represent the effective dynamics of complex systems, but estimating their drift and diffusion coefficients from data remains challenging. Standard approaches often rely on short-time trajectory increments, state-space partitioning, or repeated simulation of candidate models, which become unreliable or computationally expensive for high-dimensional systems, coarse temporal sampling, or unevenly sampled data. We introduce a data-driven calibration method based on a novel relationship between the coefficients of a stochastic reduced model and the conditional score of the finite-time transition density, defined as the gradient of the logarithm of the transition density with respect to the initial state. The resulting identity expresses derivatives of lagged correlation functions as stationary expectations over observed lagged pairs involving this conditional score and the unknown model coefficients. This formulation allows the drift and diffusion structure to be constrained directly from finite-lag statistics, without differentiating trajectories, partitioning state space, or repeatedly integrating candidate reduced models during calibration, yielding a least-squares fitting problem over stationary lagged pairs. We validate the approach on three systems of increasing complexity: an analytically tractable Cox–Ingersoll–Ross diffusion, a two-dimensional nonequilibrium diffusion with affine multiplicative noise, and a periodic soft-spin stochastic Landau–Lifshitz chain. Across these tests, the inferred models preserve the invariant statistics while reproducing finite-lag dynamical correlations. The framework provides a scalable route for learning stochastic reduced-order models from data that reproduce prescribed statistical and dynamical properties.

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

Conformal calibration and look-elsewhere effect in anomaly detection for new-physics searches

arXiv:2606.13780v1 Announce Type: cross Abstract: Machine-learned anomaly detection is reshaping searches for new physics, but it has outrun the statistics used to interpret it. A raw anomaly score has no calibrated meaning, a model that scans many regions inflates the look-elsewhere effect, and the asymptotic significances the field relies on are blind to the background mismodelling that anomaly detectors are especially prone to. We propose a calibration layer, built on conformal prediction, that turns any anomaly score into a defensible significance with distribution-free, finite-sample guarantees. Conformal prediction converts scores into valid local p-values, weighted and Mondrian variants repair the sideband-to-signal-region exchangeability failures that resonant searches suffer, and a Gross-Vitells step carries the result through to a look-elsewhere-aware global significance. The layer does two things at once. It exposes miscalibration that the standard pipeline cannot see, and it corrects it without retraining the detector. On public LHC Olympics data, a classifier develops a substructure-mass correlation that makes sideband-calibrated background p-values anti-conservative. Taken at face value, this manufactures a $\sim 46\sigma$ excess from background sculpting alone, which the label-free weighted correction removes, restoring an honest null. When run as a blind wide-mass bump hunt, the standard asymptotic and unweighted procedures fabricate $\gtrsim10\sigma$ excesses and $\approx5\sigma$ excesses even in signal-free windows, while the conformal layer raises no false alarms and its global false-positive rate is verified on background-only pseudoexperiments. The result is an auditable, detector-agnostic path from an uncalibrated score to a trials-factor-aware significance, ready to be folded into experimental anomaly searches.

21.
arXiv (CS.CV) 2026-06-11

SheafStain: Sheaf-Theoretic Schrödinger Bridge for Spatially and Biologically Coherent Virtual Staining

Current virtual staining approaches offer the potential for time- and cost-efficient biomarker quantification in cancer diagnostics and prognostics. However, patch-wise inference for gigapixel whole slide images (WSIs) fails to maintain spatial continuity, yielding artifacts that cause catastrophic mismatches with ground-truth images. Although pathology Vision Foundation Models (VFMs) offer rich representations, their self-attention causes varying global contexts to produce inconsistent embeddings for the same physical region. We formalize and validate this ``context contamination'' as a sheaf-theoretic problem where these embeddings form a presheaf that violates the gluing axiom. To address this, we propose SheafStain, a new approach that reinterprets VFM features as sheaf-like sections for spatially and biologically coherent virtual staining. Specifically, SheafStain integrates class and patch tokens into a Schrödinger Bridge framework as sheaf-like sections. While the class token anchors biological consistency, patch tokens form a per-position spatial map. A backbone co-pretrained on Hematoxylin \& Eosin (H\&E) and Immunohistochemistry (IHC) yields non-degenerate cross-stain stalks, so a single VFM feature space supervises both input conditioning and output stain alignment. Departing from prior work that evaluates on isolated $256 \times 256$ patches and either random-crops or resizes the $1024 \times 1024$ ground truth, we translate at $256 \times 256$ and evaluate on the stitched $1024 \times 1024$ outputs across HER2, ER, PR, and Ki-67. SheafStain demonstrates promising results against six prior methods while mitigating patch-boundary stitching artifacts. Code will soon be released.

22.
arXiv (CS.CL) 2026-06-12

BLUEmed: Retrieval-Augmented Multi-Agent Debate for Clinical Error Detection

Terminology substitution errors in clinical notes, where one medical term is replaced by a linguistically valid but clinically different term, pose a persistent challenge for automated error detection in healthcare. We introduce BLUEmed, a multi-agent debate framework augmented with hybrid Retrieval-Augmented Generation (RAG) that combines evidence-grounded reasoning with multi-perspective verification for clinical error detection. BLUEmed decomposes each clinical note into focused sub-queries, retrieves source-partitioned evidence through dense, sparse, and online retrieval, and assigns two domain expert agents distinct knowledge bases to produce independent analyses; when the experts disagree, a structured counter-argumentation round and cross-source adjudication resolve the conflict, followed by a cascading safety layer that filters common false-positive patterns. We evaluate BLUEmed on a clinical terminology substitution detection benchmark under both zero-shot and few-shot prompting with multiple backbone models spanning proprietary and open-source families. Experimental results show that BLUEmed achieves the best accuracy (69.13%), ROC-AUC (74.45%), and PR-AUC (72.44%) under few-shot prompting, outperforming both single-agent RAG and debate-only baselines. Further analyses across six backbone models and two prompting strategies confirm that retrieval augmentation and structured debate are complementary, and that the framework benefits most from models with sufficient instruction-following and clinical language understanding.

23.
bioRxiv (Bioinfo) 2026-06-11

HoloCell: A Generative Foundation Model for Holistic Cellular Modeling

Single-cell multi-omics technologies have recently advanced to enable the profiling of epigenomic, transcriptomic, and proteomic layers within individual cells, offering new opportunities to characterize cellular states as integrated biological systems. However, developing a unified framework that can seamlessly integrate diverse omics modalities and remain robust to heterogeneous modality missingness remains challenging. Here we present HoloCell, to our knowledge the first generative foundation model for joint representation learning and generative modeling across all three major single-cell omics modalities, i.e., epigenomics, transcriptomics, and proteomics. HoloCell contains over 860 million parameters and is pretrained on the Human-Multi-Omics-Corpus, which comprises approximately 468 million single-cell profiles across these three omics layers, corresponding to over 425 billion tokens. HoloCell introduces a simple yet biologically grounded hierarchical tokenization strategy that encodes cis-regulatory elements, genes, and proteins as structured tokens within a shared modeling framework. We evaluated HoloCell across single-omics representation learning, paired multi-omics integration, unpaired multi-omics alignment, and cross-modal generation via iterative diffusion and remasking, demonstrating its superior performance and flexibility across diverse omics tasks. From a representation perspective, HoloCell provides a unified digital mapping of cellular states across multiple omics layers, capturing cell heterogeneity as an integrated system. From a generation perspective, its iterative diffusion and remasking framework accounts for the inherently unordered nature of biological features, enabling in silico simulation of multi-omics information flow. Together, these capabilities position HoloCell as a versatile foundation model toward the emerging concept of a virtual cell, offering both systematic characterization and generative simulation of cellular systems within a unified framework.

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

Shachi: A Modular, Controllable Framework for LLM-Based Agent-Based Modeling of Emergent Collective Behavior

arXiv:2509.21862v3 Announce Type: replace Abstract: How collective behaviors emerge from the interactions of individual LLM-driven agents is a central question in artificial life, yet controlled study of these emergent dynamics has been hindered by the lack of a principled simulation framework for systematic experimentation. To address this, we introduce Shachi, a principled methodology and modular framework that decomposes an agent's cognition into core components: Configuration for intrinsic identity, Memory for contextual continuity, and Tools for extended capabilities, all orchestrated by an LLM reasoning engine. This decomposition treats each cognitive component as an independently controllable variable, enabling perturbation studies that trace how micro-level cognitive traits propagate into population-level dynamics. We investigate behavioral patterns across a 10-task benchmark spanning three levels of collective complexity. Shachi enables memory transfer across environment transitions, producing history-dependent behavioral shifts, and allows agents to simultaneously inhabit multiple environments, revealing cross-environment interference invisible in single-environment studies. Furthermore, in a real-world U.S. tariff shock case study, locally interacting agents with individually controlled cognitive components produce macro-level market dynamics directionally consistent with observed real-world outcomes. Our work provides a rigorous, open-source simulation framework for LLM-based ABM, aimed at fostering cumulative scientific inquiry into the emergent collective behaviors of interacting artificial agents.

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Nature Medicine 2026-06-10

Dual-target gene therapy in Parkinson’s disease: a multicenter phase 1 trial

Authors:

Restoring striatal dopamine synthesis is a promising gene therapy strategy for Parkinson’s disease. Previous adeno-associated virus-mediated aromatic L-amino acid decarboxylase (AADC) monotherapies remain dependent on exogenous levodopa, whereas multigene delivery is constrained by strict adeno-associated virus packaging limits. A ‘dual approach’ targeting the two rate-limiting enzymes, tyrosine hydroxylase (TH) and AADC, offers the potential for autonomous dopamine synthesis. We report the 12-month primary safety and tolerability outcomes of a multicenter, open-label, dose-escalation, phase 1 trial evaluating BBM-P002, a new adeno-associated virus vector—AAVT42—codelivering constitutively active TH and AADC. Ten participants with moderate-to-advanced Parkinson’s disease were enrolled and received bilateral intraputaminal infusions across doses of 4.0 × 1011 vg (Cohort 1; n = 1), 6.0 × 1011 vg (Cohort 2; n = 2), 1.0 × 1012 vg (Cohort 3; n = 2) and 1.2 × 1012 vg (Cohort 4; n = 5). The trial achieved its primary outcome, as BBM-P002 demonstrated a favorable safety and tolerability profile within 12 months post-treatment. No dose-limiting toxicities or drug-related serious adverse events occurred. A total of 23 adverse events were reported, all judged unrelated to BBM-P002 and primarily mild and transient. Systemic toxicity and clinically meaningful immunogenicity were absent. In conclusion, intraputaminal delivery of BBM-P002 was safe and well tolerated in this phase 1 trial, supporting continued clinical development. ClinicalTrials.gov registration: NCT05822739 . Phase 1 results reveal that BBM-P002, a dual-target gene therapy co-delivering TH and DDC, is safe and well tolerated in Parkinson’s disease, with 12-month motor improvements signaling therapeutic potential.