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01.
bioRxiv (Bioinfo) 2026-06-16

PhenoBIC: operator-free single-cell spatial phenotyping in multiplex imaging data using deep learning of cell staining patterns

Multiplex imaging is a valuable tool for spatially examining tissue microenvironments at the single-cell level to uncover biological and clinical insights. However, most multiplex image analysis workflows currently require manual intervention for cell phenotyping, which slows progress, demands human effort, and yields operator-dependent outputs. Here, we developed PhenoBIC, a pre-trained deep learning model for image classification of the multiplexed biomarker signals in a cell (Biomarker Imprint of a Cell) to classify cell phenotypes. We show that PhenoBIC (F1-score ~0.88) outperforms manual gating (widely used) and other machine learning-based computational approaches for cell marker expression classification. We validated this across multiple biomarkers, tissue sampling strategies (whole biopsies and tissue microarrays), multiplex panels, imaging platforms, and tissue types. We have released our in-house training and validation datasets of ~1.4 million manually curated cell expression ground truth labels. We have also open-sourced PhenoBIC and enabled its community-wide deployment via the QuPath interface.

02.
arXiv (CS.LG) 2026-06-17

A tensor network approach for chaotic time series prediction

arXiv:2505.17740v2 Announce Type: replace Abstract: Making accurate predictions of chaotic time series is a complex challenge. Reservoir computing, a neuromorphic-inspired approach, has emerged as a powerful tool for this task. It exploits the memory and nonlinearity of dynamical systems without requiring extensive parameter tuning. However, selecting and optimizing reservoir architectures remains an open problem. Next-generation reservoir computing simplifies this problem by employing nonlinear vector autoregression based on truncated Volterra series, thereby reducing hyperparameter complexity. Nevertheless, the latter suffers from exponential parameter growth in terms of the maximum monomial degree. Tensor networks offer a promising solution to this issue by decomposing multidimensional arrays into low-dimensional structures, thus mitigating the curse of dimensionality. This paper explores the application of a previously proposed tensor network model for predicting chaotic time series, demonstrating its advantages in terms of accuracy and computational efficiency compared to conventional echo state networks. Using a state-of-the-art tensor network approach enables us to bridge the gap between the tensor network and reservoir computing communities, fostering advances in both fields.

03.
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.

04.
arXiv (CS.LG) 2026-06-11

Online Learning for Supervisory Switching Control

arXiv:2603.14762v4 Announce Type: replace-cross Abstract: We study supervisory switching control for partially-observed linear dynamical systems. The objective is to identify and deploy a suitable controller for the unknown system by periodically selecting among a collection of $N$ candidate controllers, some of which may destabilize the underlying system. While classical estimator-based supervisory control guarantees asymptotic stability, it lacks quantitative finite-time performance bounds. Conversely, current non-asymptotic methods in both online learning and system identification require restrictive assumptions that are incompatible in a control setting, such as system stability, which preclude testing potentially unstable controllers. To bridge this gap, we propose a novel, non-asymptotic analysis of supervisory control that adapts multi-armed bandit algorithms to a control-theoretic setting. The proposed data-driven algorithm evaluates candidate controllers via scoring criteria that leverage system observability to isolate the effects of state history, enabling both detection of destabilizing controllers and accurate system identification. We present two algorithmic variants with dimension-free, finite-time guarantees, where each identifies the matching controller in $O(N \log^2 N)$ steps, while simultaneously achieving finite $L_2$-gain with respect to system disturbances.

05.
arXiv (CS.CL) 2026-06-11

"Do Not Mention This to the User": Detecting and Understanding Malicious Agent Skills in the Wild

LLM-based coding agents increasingly rely on third-party extensions called skills, which bundle natural language instructions and helper scripts that execute with full user privileges. Community registries have emerged to distribute these skills, but the security implications remain unstudied due to the absence of labeled threat data. This paper presents a systematic security analysis of 98,380 skills collected from two major registries. Through a combination of static pattern matching and dynamic behavioral verification, we identify 157 skills exhibiting confirmed malicious behavior, encompassing 632 distinct vulnerabilities across 13 attack techniques. Our analysis reveals that these threats are deliberate rather than accidental: each malicious skill contains an average of 4.03 vulnerabilities spanning multiple attack phases. We identify two dominant attack strategies with statistically significant negative correlation – credential theft via remote code execution, and agent manipulation through adversarial instructions embedded in documentation. Over half of all confirmed cases originate from a single threat actor employing templated brand impersonation at scale. We further observe that attack sophistication correlates with concealment investment, with advanced skills universally employing undocumented capabilities while also exploiting platform-native trust mechanisms. Following responsible disclosure, registry maintainers removed all 157 (100%) of the reported skills. Our dataset and detection pipeline are publicly available to facilitate future research on securing LLM agent ecosystems.

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

Visual enhancement and 3D representation for underwater scenes: a review

Underwater visual enhancement (UVE) and underwater 3D reconstruction pose significant challenges in computer vision and AI-based tasks due to complex imaging conditions in aquatic environments. Despite the development of numerous enhancement algorithms, a comprehensive and systematic review covering both UVE and underwater 3D reconstruction remains absent. To advance research in these areas, we present an in-depth review from multiple perspectives. First, we introduce the fundamental physical models, highlighting the peculiarities that challenge conventional techniques. We survey advanced methods for visual enhancement and 3D reconstruction specifically designed for underwater scenarios. The paper assesses various approaches from non-learning methods to advanced data-driven techniques, including Neural Radiance Fields and 3D Gaussian Splatting, discussing their effectiveness in handling underwater distortions. Finally, we conduct both quantitative and qualitative evaluations of state-of-the-art UVE and underwater 3D reconstruction algorithms across multiple benchmark datasets. Finally, we highlight key research directions for future advancements in underwater vision.

07.
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.

08.
arXiv (CS.LG) 2026-06-12

Foundations of Practical Quantum Advantage in Quantum-Informed Machine Learning for Predicting Chaos

arXiv:2606.13422v1 Announce Type: cross Abstract: We develop theoretical foundations for a practical quantum-advantage mechanism in quantum-informed machine learning for chaotic dynamical systems. A family of k-indexed higher-order quantum statistical priors (Q-Priors) hosts the k-point marginal of the invariant measure on n_q = kq qubits, extending the single-site construction of prior work. We prove a two-stage advantage. In the representation stage, superposition and entanglement compactly store non-factorisable spatial correlations of the invariant measure on n_q qubits. In the extraction stage, joint Bell measurements on two copies estimate any post hoc Pauli functional with a copy-pair count independent of n_q, whereas any adaptive single-copy protocol for the corresponding full-Pauli read-out requires Omega(2^(n_q)) copies; this is a provable quantum-classical separation in copy-measurement complexity. The two-copy read-out is realised in simulation and on IQM superconducting processors. Two case studies instantiate the mechanism in workflows of independent scientific value: a turbulent channel-flow study in which the two-copy read-out yields a named non-diagonal correlator of the invariant measure (the velocity-direction coherence), and a medium-range weather forecasting workflow on the European Centre for Medium-Range Weather Forecasts ERA5 reanalysis in which the diagonal k

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

On-chip semi-device-independent quantum random number generator exploiting contextuality

arXiv:2601.08392v2 Announce Type: replace Abstract: We present a semi-device-independent quantum random number generator (QRNG) based on the violation of a contextuality inequality, implemented by the integration of two silicon photonic chips. Our system combines a heralded single-photon source with a reconfigurable interferometric mesh to implement qutrit state preparation, transformations, and measurements suitable for testing a KCBS contextuality inequality. This architecture enables the generation of random numbers from the intrinsic randomness of single-photon interference in a complex optical network, while simultaneously allowing a quantitative certification of their security without requiring entanglement. We observe a contextuality violation exceeding the classical bound by more than 10{\sigma}, unambiguously confirming non-classical behavior. From this violation, we certify a conditional min-entropy per experimental round of Hmin = 0.077 +- 0.002, derived via a tailored semidefinite-programming-based security analysis. Each measurement outcome therefore contains at least 0.077 +- 0.002 bits of extractable genuine randomness, corresponding to an asymptotic generation rate of 21.7 +- 0.5 bits/s. These results establish a viable route towards general-purpose, untrusted quantum random number generators compatible with practical integrated photonic quantum networks.

10.
arXiv (quant-ph) 2026-06-19

Indefinite Quantum Causality

arXiv:2606.19438v1 Announce Type: new Abstract: In recent years, operational approaches to quantum foundations have been developed as a means of understanding the core principles and distinctive features of quantum theory. Such approaches typically view physical processes as sequences of operations, with earlier operations serving as causes of later effects. However, a growing literature is emerging on the possibility of relaxing this assumption and allowing for quantum indefiniteness in the causal order. This development stems from a variety of motivations, both fundamental and applied, including exploring the role of causality in quantum theory, the interplay between quantum theory and general relativity, and higher-order quantum computing. A prominent offshoot of this development is the emergence of indefinite causal order as a feasible resource for quantum information processing. This review provides an overview of the current state of the art in the field, covering the methodology underlying indefinite quantum causality within the so-called "process matrix formalism", outlining key results and experimental implementations, and discussing recent advances.

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

Adaptive Oscillatory-State Alignment for Time Series Forecasting

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

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

Evaluating Universal Machine Learning Force Fields Against Experimental Measurements

arXiv:2508.05762v2 Announce Type: replace-cross Abstract: Universal machine learning force fields (UMLFFs) promise to revolutionize materials science by enabling rapid atomistic simulations across the periodic table. However, their evaluation has been limited to computational benchmarks that may not reflect real-world performance. We introduce UniFFBench, a comprehensive evaluation framework featuring the MinX dataset – a diverse collection of 1,500+ mineral systems spanning 85 elements, extreme thermodynamic conditions (0–5000 K, 0–1000 GPa), and structural complexity, including partial occupancy and disorder. This diversity, combined with experimental reference values for validation, enables assessment of UMLFF generalization across chemical space and conditions substantially beyond typical training scenarios. Our systematic evaluation of six state-of-the-art UMLFFs reveals a substantial ``reality gap'': models achieving impressive performance on computational benchmarks often fail when confronted with experimental complexity. Even the best-performing models exhibit higher density prediction error than the threshold required for practical applications. We observe disconnects between simulation stability and mechanical property accuracy, with prediction errors correlating with training data representation rather than the modeling method.

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

Hierarchical Multi-Modal Retrieval for Knowledge-Grounded News Image Captioning

Traditional image captioning methods often struggle to generate comprehensive, context-rich descriptions, especially for details not directly observable from visual cues. To overcome this, we propose a novel retrieval-augmented image captioning framework that generates captions with deeper insights, such as object attributes, event context, and underlying significance, by leveraging external knowledge. Our approach features a hierarchical multi-modal article retrieval mechanism that moves beyond monolithic text entities. This retrieval considers article structure-aware features, including weighted textual components (e.g., headlines, body sections) and visual placement patterns, alongside multi-faceted similarity computations (content–visual, visual–visual, and discourse positioning). A subsequent contextual relevance refinement stage further enhances the retrieved information. The retrieved articles then serve as the knowledge base for caption generation: first, a VLM generates a concise image description; second, we segment relevant information from the retrieved articles based on this description; and finally, an LLM utilizes both the description and extracted knowledge to generate a comprehensive, contextually detailed caption. We participated in the ACM Multimedia EVENTA 2025 Challenge and achieved 5th place with an overall score of 0.2824 on the private test set of the OpenEvent-V1 dataset. Source code is publicly released at https://github.com/mf0212/EVENTA-Challange.

14.
arXiv (quant-ph) 2026-06-24

Spectrally engineered collinear type-0 SPDC source with enhanced spectral brightness for entanglement distribution

arXiv:2606.24036v1 Announce Type: new Abstract: Entangled photon sources with high spectral brightness are important resources for photonic quantum information processing, particularly in quantum communication and quantum networking where usable photon flux of entangled photons is often constrained by channel loss and source inefficiency. Here, we demonstrate a spectrally engineered type-0 spontaneous parametric down-conversion (SPDC) source with enhanced spectral brightness for entanglement distribution. By pumping a 30-mm ppKTP crystal with an ultra-narrowband laser slightly detuned from degeneracy, photon-pair generation is concentrated into a narrow spectral bandwidth while retaining the strong nonlinear interaction of type-0 phase matching. The source produces a coincidence rate of 44.6 kHz corresponding to a detected spectral brightness of 0.507 MHz/mW/nm. We further integrate the source into a Sagnac interferometer to generate polarization-entangled photon pairs and demonstrate entanglement distribution through a 2.56 km free-space round-trip channel. Our results show that spectral engineering provides a practical route to compact, spectrally bright entangled-photon sources for quantum communication applications.

15.
arXiv (CS.AI) 2026-06-12

GeoDial: A Multimodal Conversational Tutoring Dataset for Geometry Problem-Solving with Visual Tutor Turns

arXiv:2606.12419v1 Announce Type: cross Abstract: Several educational domains rely heavily on diagrams and visual cues, yet most existing tutoring datasets are limited to text-only interactions. This limits the development of AI tutors that can teach in visually grounded ways used by human instructors. Thus, we introduce GeoDial, a multimodal tutoring dataset of over 1.3K teacher-student dialogs in the domain of geometry collected from experienced math teachers, where instructional turns are explicitly grounded in diagram highlights. We propose a scalable annotation protocol that integrates dialog acts, visual highlighting, and feedback, enabling fine-grained supervision of both language and visual tutoring behavior. To illustrate the challenges posed by this setting, we fine-tune several vision-language models on GeoDial and evaluate their ability to generate tutoring utterances and diagram highlights. While supervised fine-tuning substantially improves the quality of generated dialog, it struggles to produce accurate diagram highlights, revealing a key limitation of current methods and highlighting the need for approaches that more effectively integrate visual reasoning with pedagogical interaction.

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

Toten: Knowledge-Based Ontological Tokenization Of Physical Quantities And Technical Notation In Brazilian Portuguese

Byte-Pair Encoding tokenization is statistically efficient for vocabulary compression, but semantically blind to structured technical entities, fragmenting physical quantities, numbers, units, and symbolic expressions into lexically arbitrary subwords. We present TOTEN, a knowledge-based ontological tokenization framework that replaces statistical derivation with declarative classification grounded in a formal ontology of engineering entities (OEE). We formalize TOTEN as the triple : the ontology gathers types, structural principles, composition relations, and preservable invariants; the classification function maps raw text into typed regions; and the instantiator family yields a self-descriptive structured representation. Robustness derives from deterministic coupling with three external oracles: Pint (dimensional), Unicode Character Database (typographic), and RSLP (Portuguese morphology). Intrinsic evaluation covers four properties verifiable by construction – ontological atomicity, dimensional equivalence, typographic robustness, and numerical reconstruction – over an internal, physically validated benchmark (EngQuant, N=800) and four Brazilian Portuguese external corpora (N=1771 eligible cases). We also report detection recall, distinguishing coverage from conditional atomicity. Against eight state-of-the-art baselines, TOTEN achieves unit ontological atomicity in all contrasts and numerical reconstruction of 0.775-0.904 on external corpora, vs. 0.627-0.703 for the best baseline (Quantulum3); on EngQuant, 0.780 vs. 0.340. Differences are statistically significant (McNemar with Holm correction). Spearman correlation between internal and external rankings confirms concurrent validity of the control benchmark. Dimensional equivalence shows statistical parity with Pint, the oracle from which the system inherits dimensional authority.

17.
bioRxiv (Bioinfo) 2026-06-20

SAbDab2: The structural antibody database in the age of machine learning

The Structural Antibody Database (SAbDab) is a publicly available repository of experimentally determined antibody structures, first released in 2013. Explicit support for single-domain antibodies was added in 2021, with SAbDab-nano. Recently, increasing interest in antibodies has led to a proliferation of novel antibody formats, while simultaneous advances in machine learning have increased demand for standardised, high-quality structure data. Here, we present SAbDab2, re-engineered for the machine-learning age. It introduces support for a variety of new formats, and makes it easy to retrieve and compare all known structures of a given antibody. In addition, SAbDab2 provides ready access to ML-grade structures of antibody and antibody–antigen-complexes, with standardised, versioned train/test splits. These will be updated every six months going forward, and are available at https://zenodo.org/records/20083995. SAbDab2 itself is updated weekly and is freely available at https://sabdab2.opig.stats.ox.ac.uk.

18.
arXiv (CS.CV) 2026-06-16

KeepLoRA++: Continual Learning with Layer-Scaled Residual Gradient Adaptation

Continual learning for pre-trained vision-language models requires balancing three competing objectives: retaining pre-trained knowledge, preserving knowledge from a sequence of learned tasks, and maintaining the plasticity to acquire new knowledge. This paper presents KeepLoRA++, balancing these objectives through a unified dual-dimensional knowledge retention mechanism. We analyze knowledge distribution of Transformer architecture from both inter-layer and intra-layer perspectives. The inter-layer perspective examines how retention is distributed across layers, while the intra-layer perspective focuses on the parameter space within each layer. Our analysis reveals a structural property: general transferable knowledge is mainly encoded in the shallow layers and the principal subspace of the parameters, while task-specific adaptations are localized in the deep layers and the residual subspace. Motivated by this insight, KeepLoRA++ introduces a layer-scaled residual gradient adaptation method. New tasks are learned by restricting LoRA parameter updates to the residual subspace, combined with a shallow-to-deep layer scaling, to prevent interference with previously acquired capabilities. Specifically, the gradient of a new task is projected onto a subspace orthogonal to both the principal subspace of the pre-trained model and the dominant directions of previous task features, while simultaneously assigning smaller update magnitudes to shallow layers and larger ones to deeper layers. Our theoretical analysis and empirical evaluations confirm that KeepLoRA++ successfully balances these three competing objectives, consistently outperforming representative baselines across image classification, visual question answering, and video understanding tasks.

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

EmoFSM: A Finite State Machine for Emotional Support Conversation

Emotional support conversation (ESC) aims to alleviate people's emotional distress through effective conversations. Although large language models (LLMs) have made remarkable progress in ESC, most of these studies may not define the diagram from a state-model perspective, thereby providing a suboptimal solution for long-term satisfaction. To address such an issue, we leverage the Finite State Machine (FSM) on LLMs, and propose a framework called EmoFSM. Our framework allows a single LLM to bootstrap the planning during ESC, and self-reason the seeker's emotion, support strategy, and the final response upon each conversation turn. Substantial experiments in ESC datasets suggest that EmoFSM outperforms many baselines, including direct inference, self-fine, chain of thought, finetuning, and externally supported methods, even those with many more parameters.

20.
arXiv (CS.CL) 2026-06-18

Rethinking Reward Supervision: Rubric-Conditioned Self-Distillation

Post-training of reasoning language models is commonly driven by supervised distillation and reinforcement learning with verifiable rewards. Distillation often relies on chain-of-thought annotations that are expensive to obtain and may themselves be noisy, incomplete, or partially incorrect; even when the final solution is correct, an imperfect rationale can interfere with learning. Reinforcement learning with verified rewards, on the other hand, typically compresses evaluative feedback into a scalar signal, obscuring which aspects of a response should be improved. We propose Rubric-Conditioned Self-Distillation, a framework that incorporates rubrics as structured, fine-grained feedback for on-policy self-distillation. Our method conditions the teacher model on criterion-level rubrics and uses it to provide token-level guidance on the student's own sampled trajectories. This design avoids treating a single reference rationale as the sole supervision target. Instead, rubrics specify what a strong response should satisfy, enabling more fine-grained credit assignment over the reasoning process than scalar reward optimization. We instantiate this framework with a two-stage pipeline that first learns to generate task-specific rubrics and then trains a rubric-guided reasoner. We evaluate on a diverse suite of science reasoning benchmarks and results show that rubric-conditioned self-distillation effectively converts rubric-level criteria into token-level guidance over the reasoning process, surpassing GRPO by 1.0 points and OPSD by 0.9 points on average.

21.
Nature Medicine 2026-06-08

Effects of SGLT2 inhibition on incident heart failure in carriers of cardiomyopathy-associated genetic variants

Although the beneficial effects of sodium–glucose cotransporter 2 (SGLT2) inhibition in heart failure (HF) have been well established, it is unknown whether SGLT2 inhibition confers benefit in carriers of rare variants in cardiomyopathy-associated genes. Here we evaluated whole-exome sequencing data from the randomized DECLARE-TIMI 58 trial, in which adults with type 2 diabetes and increased cardiovascular risk were randomized to dapagliflozin or placebo treatment. Pathogenic or likely pathogenic variants (P/LP) in high-confidence cardiomyopathy genes were identified, and treatment effects on hospitalization for HF (HHF) were compared between carriers of such variants and noncarriers. Among 12,685 patients for whom sequence data were obtained, 121 carried a cardiomyopathy variant (76 dilated cardiomyopathy, 25 hypertrophic cardiomyopathy and 25 arrhythmogenic cardiomyopathy). Over a median follow-up of 4.2 years, dapagliflozin lowered the risk of HHF more strongly in carriers (hazard ratio 0.18, 95% confidence interval 0.04–0.86) than in noncarriers (hazard ratio 0.70, 95% confidence interval 0.57–0.86; P interaction 0.03). Absolute risk reduction was 13.0% in carriers and 1.0% in noncarriers (P interaction 0.03). Most carriers (82%) had no prior HF, and in carriers without prior HF, treatment with dapagliflozin reduced the absolute risk of HHF by 12.8%, compared with a reduction of 0.6% in noncarriers (P interaction 0.01). The findings from this cohort of older and high-risk patients raise the possibility that SGLT2 inhibitor treatment should be started early to prevent HF in individuals who carry P/LP cardiomyopathy variants. These results need to be confirmed in a prospective, dedicated trial of preventive HF treatments in carriers of P/LP cardiomyopathy-associated variants. In a whole-exome sequencing analysis, the beneficial effects of the SGLT2 inhibitor dapagliflozin in reducing the risk of future heart failure hospitalization in individuals with type 2 diabetes were markedly greater in individuals who carried a cardiomyopathy-associated genetic variant compared with noncarriers, suggesting a personalized preventative therapy based on genetic information.

22.
bioRxiv (Bioinfo) 2026-06-11

OCOO-T : A SIMPLE AND SCALABLE VIRTUAL CELL MODEL FOR TRANSCRIPTIONAL PERTURBATION RESPONSE PREDICTION

Predicting single-cell transcriptional responses to genetic, chemical and cytokine perturbations is a fundamental challenge in computational biology and AI Virtual Cell (AIVC) modeling, with direct implications for drug discovery and the elucidation of gene regulatory networks. Existing approaches often rely on auxiliary cell-state encoders, hierarchical variational autoencoders, dedicated Transformer encoder-decoder modules, or gene-interaction priors to compress high-dimensional expression profiles into latent representations. While effective, these designs increase architectural complexity and may limit scalability and generalizability. This paper introduces OCOO-T, a minimalist flow-matching-based AIVC model for transcriptional perturbation response prediction. OCOO-T utilizes a vanilla Transformer stack that operates directly on continuous gene expression profiles and formulates perturbation response prediction as a continuous-time denoising process. Perturbation embeddings, dosage information, and cell-line/cell-type specificity are integrated through adaptive layer normalization and in-context tokens. Comprehensive evaluations on Tahoe100M, Replogle, and PBMC benchmarks demonstrate that OCOO-T achieves state-of-the-art performance across diverse perturbations and cell types while effectively scaling to long transcriptional profiles through patching and depatching of cellular contexts. By leveraging the simplicity of Transformer-based denoising for single-cell omics, OCOO-T provides an effective and scalable framework for in-silico cellular simulation.

23.
arXiv (CS.AI) 2026-06-17

Gaussian DP for Reporting Differential Privacy Guarantees in Machine Learning

arXiv:2503.10945v3 Announce Type: replace-cross Abstract: Current practices for reporting differential privacy (DP) guarantees for machine learning (ML) algorithms such as DP-SGD provide an incomplete and potentially misleading picture. For instance, if only a single $(\varepsilon, \delta)$ is known about a mechanism, standard analyses show that there could exist highly accurate inference attacks against training data records, when, upon a more careful analysis, such accurate attacks do not exist for most practical mechanisms. In this position paper, we argue that using _non-asymptotic_ Gaussian Differential Privacy (GDP) as the primary means of communicating DP guarantees in ML avoids these potential downsides. Using two recent developments in the DP literature: (i) open-source numerical accountants capable of computing the privacy profile and $f$-DP curves of DP-SGD to arbitrary accuracy, and (ii) a decision-theoretic metric over DP representations, we show how to provide non-asymptotic bounds on GDP using numerical accountants, and show that GDP can capture the entire privacy profile of DP-SGD and related algorithms with virtually no error, as quantified by the metric. To support our claims, we investigate the privacy profiles of state-of-the-art DP large-scale image classification, and the TopDown algorithm for the U.S. Decennial Census, observing that GDP fits their profiles remarkably well in all cases. We conclude with a discussion on the strengths and weaknesses of this approach, and discuss which other privacy mechanisms could benefit from GDP.

24.
medRxiv (Medicine) 2026-06-16

MRMU: A New Paradigm for Mendelian Randomization by Accounting for Measured Covariates and Unmeasured Confounders

Mendelian randomization (MR) is a powerful approach for causal inference, however, its reliability is frequently compromised by unadjusted covariates and unmeasured confounders, such as unmeasured pleiotropy and sample structure. To address these challenges, we introduce MRMU, a novel paradigm for the MR framework. Unlike traditional single-variable or multivariable MR methods, MRMU selects instrumental variables only from the exposure of interest and estimates one exposure effect at a time, while jointly accounting for measured covariates and unmeasured confounders. This design improves the reliability of MR analyses. In simulations and real data, MRMU achieved better type I error control, higher statistical power, and more accurate effect estimation than existing MR methods. Applying to coronary artery disease (CAD), MRMU identified robust cardiometabolic risk factors, including LDL-C, APOB, systolic blood pressure, body mass index, and smoking initiation, with consistent evidence across multiple CAD datasets. In contrast, traits such as HDL-C, height, and educational attainment, which were found to be significant by existing MR methods, were no longer supported by MRMU. MRMU further supported blood pressure-related traits, rather than lipid traits, as the more relevant pathway linking urate to CAD. Finally, by integrating large-scale plasma proteomics data, MRMU identified candidate CAD drug targets beyond established HMGCR- and PCSK9-related pathways, highlighting its utility for therapeutic target prioritization.

25.
arXiv (CS.CL) 2026-06-12

LoHoSearch: Benchmarking Long-Horizon Search Agents Beyond the Human Difficulty Ceiling

Search agent benchmarks exemplified by BrowseComp have rapidly saturated over the past year, with the strongest models surpassing 90% accuracy. Since these benchmarks are predominantly human-authored, annotators lack a global perspective on entity statistics and cannot systematically maximize search space size and structural complexity. This creates a difficulty ceiling that is hard to break. To address this, we introduce LoHoSearch (Long-Horizon Search Agents), a challenging benchmark comprising 544 human-verified questions across 11 domains. LoHoSearch is constructed via an automated pipeline built upon a knowledge graph covering over 7 million Wikipedia entities, which selects relations with large search spaces and assembles them into structurally complex questions with KG-verified unique answers. Our evaluation demonstrates that even the strongest model achieves only 34.74% accuracy, and existing context management strategies (best +6.8%) yield far smaller gains than on prior benchmarks. LoHoSearch provides a more demanding standard for evaluating long-horizon reasoning and context management in search agents.