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01.
arXiv (quant-ph) 2026-06-11

Single Photon Cross-Phase Shifts Can Be Enhanced by Localization in both Frequency and Time

arXiv:2606.11516v1 Announce Type: new Abstract: Single-photon optical nonlinearities face a fundamental trade-off: maximum nonlinearity requires both spectral resonance (narrow bandwidth) and high peak intensity (short duration), constraints that are incompatible due to the time-energy uncertainty relation. We demonstrate experimentally that this limitation does not need to exist in cases involving post-selection. We measure a cross-phase shift (XPS) produced by a resonant photon from a narrow-band source that is first transmitted through a cold atomic cloud and then localized in time through detection. The peak size of this XPS is greatly enhanced compared to that of Gaussian single-photon-level pulses without post-selection, benefiting from the narrow bandwidth of the resonant prepared state and the high intensity of the post-selected state simultaneously. We measure enhancements in the peak XPS of 6$\pm$1 at an optical depth (OD) of 2.4$\pm$0.1, and our results are in qualitative agreement across a range of optical depths with the recently developed weak value theory of atomic excitation [Thompson et al., APL Quantum 2, 036108 (2025)] for such post-selected photons. This work uncovers new consequences of having simultaneous knowledge of frequency and time, raising new foundational questions about how a particle behaves, and interacts with other systems, when its preparation and post-selection are non-commuting.

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

LegalHalluLens: Typed Hallucination Auditing and Calibrated Multi-Agent Debate for Trustworthy Legal AI

AI systems deployed in legal workflows hallucinate at rates that aggregate metrics report at ~52%, but this average conceals where errors concentrate and in which direction they run, leaving compliance officers without an actionable signal for trustworthy deployment. We present LegalHalluLens, an auditing framework with three components: typed hallucination profiles across four legally-motivated claim categories (numeric, temporal, obligation/entitlement, factual) over CUAD (Hendrycks et al., 2021); a Risk Direction Index (RDI) that reduces omission-versus-invention bias to a single deployment-comparable scalar; and a typed debate pipeline calibrated to both magnitudes and directions. Across 510 contracts and 249,252 clause-level instances we measure a within-model gap of approximately 38-40 pp between obligation/numeric and temporal claims that aggregate reporting hides, and show that two systems with matched 52% rates can carry opposite RDIs. The debate pipeline reduces fabricated detections by 45% with per-category gains tracking the diagnosis, matching commercial APIs with a substantially smaller backbone (4B active parameters). Typed profiles and RDI surface failure modes that aggregate metrics hide; we further show these diagnostics serve as calibration inputs for multi-agent debate pipelines, where Skeptic challenges and asymmetric gates targeted at measured failure modes outperform generically-tuned debate. The framework supports direction-aware procurement, accountability, and agent design for legal AI deployed in the wild.

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

MENTOR: Reinforcement Learning via Flexible Teacher-Optimized Rewards for Tool-Use Distillation

Distilling the tool-use capabilities of large language models (LLMs) into small language models (SLMs) is essential for their practical application. The predominant approach, supervised fine-tuning (SFT), suffers from poor out-of-domain (OOD) generalization due to its rigid alignment with static teacher trajectories. While reinforcement learning (RL) offers an alternative, the capacity limitations of SLMs pose a severe dilemma: sparse outcome rewards provide insufficient guidance, whereas strict trajectory matching imposes overly restrictive constraints. To bridge this capacity-driven gap, we propose MENTOR, which introduces a flexible yet process-aware reward structure. Instead of enforcing rigid replication, MENTOR uses the teacher's reference to guide tool-use behavior, balancing behavioral alignment with downstream performance. Extensive experiments on controlled executable-tool benchmarks demonstrate that MENTOR improves OOD tool-use performance compared to SFT and strict RL baselines. Our findings suggest that within verifiable tool-use environments, flexible tool-use alignment offers a more effective approach than strict trajectory replication for developing adaptable small models.

04.
bioRxiv (Bioinfo) 2026-06-21

Antibody-Antigen Affinity Prediction with Chain-Aware Protein Language Modeling

Motivation: Antibody-antigen affinity determines which antibodies advance in therapeutic discovery, repertoire analysis and affinity maturation, but experimental measurements are sparse relative to the scale of sequence libraries. Structure-based predictors can exploit interface geometry when reliable complexes are available, yet early discovery often requires ranking many heavy-light chain pairs against antigens for which no complex structure exists. Existing sequence-based models are scalable, but frequently compress heavy and light chains into a single antibody representation or concatenate antibody and antigen features obscuring the chain-specific and epitope-specific signals that drive binding. Results: We present AbAffinity, a sequence-only chain-aware three-stream architecture that maintains heavy chain, light chain and antigen as distinct streams. It integrates frozen ESM-2 embeddings with heavy-chain CDR-focused pooling, heavy-light self-attention, adaptive fusion gating and gated cross-attention, training only a compact interaction module. On the SAAINT-DB benchmark, AbAffinity achieves strong predictive performance under ten-fold cross-validation and maintains robust accuracy on novel antigens. It consistently outperforms recent sequence-based models across external benchmarks including SAbDab, AB-Bind and SKEMPI 2.0. Ablation studies highlight the contributions of chain-specific representations, CDR-focused pooling and the gated interaction pathway. Integrated Gradients attributions recover known paratope and epitope residues at structurally validated interfaces. AbAffinity provides a lightweight, explainable sequence-first framework for antibody triage and prioritisation when structural information is limited or unavailable.

05.
medRxiv (Medicine) 2026-06-11

Large-scale proteomics and timing of hypertensive disorders of pregnancy

Background: Hypertensive disorders of pregnancy (HDP) may first be diagnosed antepartum, during labor, or postpartum. We utilized untargeted large-scale proteomics to identify pathways associated with HDP based on timing of onset. Methods: We performed a nested case-control study comparing differential protein expression, from the SomaScan 7K platform, based on timing of onset of HDP versus controls (referent) using first-trimester samples from the NuMoM2b-Heart Health Study, a multi-site cohort that followed nulliparous individuals from the first trimester. Associations of proteins with timing of onset of HDP, adjusted for co-variates, were assessed using logistic regression q value-based false discovery rates and pathway enrichment and differential expression analysis were conducted. Results: Of 1628 individuals included, 678 had HDP, of which 67% manifested antepartum (AP), 29% intrapartum (IP), and 3% postpartum (PP). After adjusting for co-variates, compared to controls, 698 proteins, 39 proteins, and 144 proteins were differentially expressed in those with HDP according to AP, IP, PP onset, respectively. There was little overlap in individual protein expression based on timing of HDP. Pathway enrichment and graphical summary analyses suggested distinct processes. Specifically, there was downregulation of angiogenic proteins in AP HDP, downregulation of immune-related proteins in IP HDP, and upregulation of complement activation promoting fibrotic changes leading to cardiac dysfunction in PP HDP. Conclusion: There are differences in first-trimester protein expression based on whether HDP first manifests AP, IP or PP. This raises the possibility that there may be distinct mechanistic phenotypes that could uniquely inform diagnostic and therapeutic targets for HDP.

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

Learning Credal Ensembles via Distributionally Robust Optimization

arXiv:2602.08470v3 Announce Type: replace Abstract: Credal predictors are models that are aware of epistemic uncertainty and produce a convex set of probabilistic predictions. They offer a principled way to quantify predictive epistemic uncertainty (EU) and have been shown to improve model robustness in various settings. However, most state-of-the-art methods mainly define EU as disagreement caused by random training initializations, which mostly reflects sensitivity to optimization randomness rather than uncertainty from deeper sources. To address this, we define EU as disagreement among models trained with varying relaxations of the i.i.d. assumption between training and test data. Based on this idea, we propose CreDRO, which learns an ensemble of plausible models through distributionally robust optimization. As a result, CreDRO captures EU not only from training randomness but also from meaningful disagreement due to potential distribution shifts between training and test data. Empirical results show that CreDRO consistently outperforms existing credal methods on tasks such as out-of-distribution detection across multiple benchmarks and selective classification in medical applications.

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

Rethinking One-Step Image Editing through ChordEdit: Reproduction, Simplification, and New Insights

One-step image editing is important for making text-guided editing fast, practical, and easy to deploy, but its underlying mechanism is still not fully understood. We revisit ChordEdit through reproduction, ablation, and simplification. Our analysis shows that a) the chord window $\delta$ largely acts as an effective timestep shift from $t$ to $t - \delta$; b) chord transport acts on high-noise images and mainly performs low-frequency semantic editing; and c) proximal alignment acts on low-noise images and complements it by adding high-frequency target details. In this view, ChordEdit naturally decomposes editing into a coarse low-frequency transport stage and a fine high-frequency alignment stage. These findings suggest a path toward prompt-conditioned dynamic timestep selection for adaptive image editing. All code and results can be found at \href{https://github.com/Harvard-AI-and-Robotics-Lab/ChordEdit-Reproduction}{link}.

08.
arXiv (CS.CV) 2026-06-19

FUSE: Frequency-domain Unification and Spectral Energy Alignment for Multi-modal Object Re-Identification

Despite significant progress in multi-modal Re-Identification (ReID), existing methods tend to emphasize low-frequency cues. Consequently, they focus on attributes such as color, illumination, and coarse appearance, while overlooking mid and high-frequency structures that encode geometric, textural, and identity-discriminative details. This imbalance leads to incomplete spectral representations and unstable cross-modal alignment. To overcome these limitations, we introduce FUSE, a frequency-domain framework that reformulates multi-modal ReID as a two-stage process of spectral disentanglement and energy alignment. The proposed Spectral Decomposition Module (SDM) adaptively partitions features into low, mid, and high-frequency subspaces, enabling hierarchical spectral modeling. The Cross-Modal Alignment Module (CAM) further enforces energy alignment and subspace complementarity across modalities via frequency-consistency regularization. In addition, FUSE incorporates learnable frequency modulation to enhance robustness under varying illumination and heterogeneous sensor conditions. Extensive experiments on RGBNT201, RGBNT100, and MSVR310 show that FUSE achieves 9.1\% mAP and 9.5\% Rank-1 improvements, establishing an interpretable frequency-domain paradigm for multi-modal representation learning.

09.
arXiv (CS.AI) 2026-06-17

DiagFlowBench: Evaluating How Language Models Handle Off-Procedure Inputs in Grounded Diagnostic Dialogue

arXiv:2606.17904v1 Announce Type: new Abstract: Language models increasingly serve as advisory systems in maintenance operations. To prevent hallucination, recent systems ground these models in procedural documentation to constrain them to approved steps. In practice, however, operator queries frequently stray from this path, requiring models to recognise out-of-scope inputs mid-conversation, a dynamic that current benchmarks rarely prioritise. We introduce DiagFlowBench, a dataset of 50 industrial diagnostic flowcharts from a consumer manufacturer converted into 1,676 multi-turn conversations that contrast compliant with out-of-scope utterances. Evaluating a panel of ten commercial and open-weight models reveals high variability in abstention rates, with models commonly selecting a real but contextually inadequate step rather than fabricating facts. The inherent plausibility and authority of this mapped but wrong advice exposes a challenging vulnerability for grounding systems.

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

A Dual-Branch Collaborative Framework for Joint Optimization of Underwater Image Enhancement and Object Detection

Due to wavelength dependent light absorption and scattering, underwater images usually suffer from color distortion and blurred details, which limits underwater object detection performance. Existing underwater image enhancement methods mainly focus on visual quality improvement, while it is still difficult to balance enhancement quality, processing efficiency, and downstream detection performance. Therefore, this paper proposes an efficient dual-branch underwater image enhancement framework for object detection. The detail enhancement branch improves brightness and local contrast to recover texture details in dark regions. The color restoration branch uses adaptive compensation to reduce color distortion and improve color gradation. By combining the complementary outputs of the two branches, the proposed framework provides clearer and more informative images for object detection. On the UIEB and EUVP datasets, the proposed method achieves UIQM scores of 2.249 and 2.576. When applied to the YOLOv8 detection task on the URPC dataset, the proposed method improves mAP50 by 2.1\% compared with the baseline. Extensive experiments show that our method improves object detection in complex underwater scenes, while balancing enhancement quality and processing efficiency.

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

Dual-Stance Evaluation of Sycophancy: The Structure of Agreement and the Limits of Intervention

Activation steering can shift LLM behaviour, but standard evaluations do not typically test whether a sycophancy-reduction direction also suppresses agreement with factually correct statements. We introduce dual-stance evaluation, which tests both stances of each topic, and apply it to centroid-difference steering on Llama-3-8B-Instruct. We find a dissociation: the model represents sycophantic and factual agreement in geometrically distinct subspaces, yet the steering direction projects equally onto both and cannot differentially target either. The direction accordingly reduces agreement with factually correct statements (e.g. that the Earth is round) as well as sycophantic ones. All other static properties of the two activation groups are matched, suggesting the behavioural dissociation arises from generation dynamics or from finer-grained structure that residual-stream analysis cannot resolve. The pattern illustrates a general gap: representations that are readable from activations may not be writable through them.

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

ProcessThinker: Enhancing Multi-modal Large Language Models Reasoning via Rollout-based Process Reward

Visual question answering increasingly requires multi-step reasoning. Recent post-training with reinforcement learning under verifiable rewards (RLVR) and Group Relative Policy Optimization (GRPO) can improve multimodal reasoning, but most approaches rely on sparse outcome-only rewards. As a result, they struggle to tell whether an incorrect answer comes from a small mistake late in the reasoning or from an unhelpful trajectory from the start. A common solution is to train a process reward model (PRM) for step-level supervision, but this typically requires large-scale high-quality chain-of-thought annotations and additional training cost. We propose ProcessThinker, a practical post-training pipeline that provides step-level process rewards without training an explicit PRM. ProcessThinker first rewrites reasoning traces into a step-tagged format for cold-start supervised fine-tuning, then applies GRPO with a standard format reward and our rollout-based process reward. Concretely, for each intermediate step, we sample multiple continuations from that step and use the empirical success rate (final-answer verification) as the step reward. This gives dense credit assignment and encourages reasoning steps that more reliably support a correct conclusion, helping reduce inconsistent or self-contradictory progress across steps – a key issue in logical reasoning. Across four challenging video benchmarks (Video-MMMU, MMVU, VideoMathQA, and LongVideoBench), ProcessThinker consistently improves over the baseline model Qwen3-VL-8B-Instruct

13.
arXiv (CS.AI) 2026-06-24

ASALT: Adaptive State Alignment for Lateral Transfer in Multi-agent Reinforcement Learning

arXiv:2606.24601v1 Announce Type: new Abstract: Multi-agent reinforcement learning (MARL) addresses the problem of training multiple agents that pursue collaborative, competitive, or mixed objectives. Prior work has investigated transfer learning between source and target domains in MARL; however, the majority of existing approaches impose the constraint that the dimensionalities of the observation space and the global state space must be identical across domains. In this paper, we introduce a method that explicitly accommodates mismatched state-space dimensionalities between source and target domains. The proposed approach, ASALT, incorporates both observation-level and state-level adapters that map the target-domain observations and global states into a shared embedding space, thereby enabling more effective transfer of knowledge across both actors and critics. These adapters can generate embeddings that support efficient strategy transfer across heterogeneous domains. Experimental results on multiple configurations in standard benchmark environments demonstrate that ASALT surpasses existing baselines in terms of sample efficiency and global return in cooperative settings, but its effectiveness depends on the degree of mismatch between source and target domains. Furthermore, our findings indicate that ASALT mitigates negative transfer, which frequently constitutes a major obstacle when transferring policies between domains with differing observation and action spaces.

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

In-Domain Supervised Pathology Report Classification: A Reproducible Pipeline from Data Curation to Production-Matched Evaluation

We introduce an in-domain supervised pipeline designed to counter the out-of-distribution performance drop that hampers supervised biomedical NLP models, a problem observed when models trained on pathology reports are moved across cancer registries. Our contribution is a reproducible recipe for training a supervised classifier from routinely collected cancer registry data. It describes how to build the in-domain training set and a production-matched holdout, and to choose operating points that keep the false-negative rate (FNR) very low while keeping reviewer workload manageable. The pipeline standardizes data curation with facility-stratified sampling and separate handling of reports linked to registry cases, and includes a blinded manual audit to estimate positive-case prevalence and label noise. On a 418k-report holdout set, the Kentucky model achieved FNR 0.003 and false-positive rate (FPR) 0.097, improving over the Seattle-trained MOSSAIC OncoID baseline (FNR 0.010, FPR 0.183) and raising F1 from 0.860 to 0.922. In a blinded manual review of 600 reports, estimated positive prevalence declined from 0.500 to 0.398, indicating substantial label noise with errors concentrated in rare primary sites.

15.
medRxiv (Medicine) 2026-06-11

Foundation model-based tool for automated ulcerative colitis histology scoring demonstrates non-inferiority to pathologists across multiple scoring indices

In clinical trials for ulcerative colitis (UC), pathologists assess disease severity through standardized histological indices, including the Geboes Score, Robarts Histopathology Index (RHI), and Nancy Histologic Index (NHI). Despite strong associations with clinical outcomes, histologic scoring suffers from inter- and intra-reader variability, and consensus criteria for histologic remission remain uncertain. Through a consortium approach, we developed an artificial intelligence-based measurement (AIM) tool for scoring histology in UC mucosal biopsies (AIM-HI UC). This model, trained on a large dataset of UC biopsies (N=10,230), utilizes additive multiple instance learning models leveraging PLUTO, a pathology foundation model, that predict each of the Geboes subgrades, from which the Geboes grade-level score, RHI, and NHI can be calculated. Evaluation of this model on a standalone verification set including clinical trial specimens established algorithm non-inferiority and/or superiority relative to standard qualified pathologists through comparison of algorithm-consensus and pathologist-consensus agreement metrics (non-inferior if difference >-0.1, superior if difference >0, inclusive of confidence intervals). AIM-HI UC was determined to be non-inferior to pathologists (N=3) for the prediction of all seven Geboes subgrades, grade-level Geboes, RHI, NHI, histologic improvement (GS

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

ResEdit: Residual embeddings for precise generative image editing

Conditional diffusion image generators can be repurposed for editing through inversion, without the need for large-scale paired fine-tuning data. However, producing high-quality, targeted edits while maintaining image identity and global consistency remains challenging, as weakly conditioned inversion often embeds conflicting image features into the noise. We demonstrate that incorporating a residual image encoding as additional conditioning enables both improved identity preservation and better editability. We optimize this residual encoding to provide a strong conditioning signal for reconstruction, thereby reducing the reliance on inversion and susceptibility to its aforementioned pitfalls. To ensure this residual does not interfere with desired edits, we incorporate a gradient reversal-based optimization strategy that disentangles the residual from the edited condition. We illustrate our method's ability to produce high-fidelity results across precise intrinsic-based editing and relighting, and show proof-of-concept text-guided manipulation.

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

MLLMs Get It Right, Then Get It Wrong: Tracing and Correcting Late-Layer Textual Bias

When vision contradicts text, multimodal large language models (MLLMs) consistently favor text, even when images provide clear evidence otherwise. This bias poses risks for applications requiring visual grounding, yet its cause remains unclear. In this paper, we uncover a surprising finding: models often get it right initially, forming correct vision-based predictions in their intermediate layers, before changing their minds and favoring text in the final output. We call this "late-layer textual override". The visual information is encoded, it simply does not survive to the output. More intriguingly, we find that how predictions change reveals whether they're correct: 85% of failures shift toward text, while 89% of successes shift toward vision. This directional signature enables a simple but powerful intervention: when we detect a confident visual prediction being suppressed, we restore it. We propose CALRD (Conflict-Aware Layer Reference Decoding), a training-free method that recovers overridden predictions at inference time. Experiments across five MLLMs of varying architectures demonstrate up to 9.4% absolute improvements on conflict benchmarks while largely preserving standard performance, without training or external knowledge. It recovers what the model already knew but failed to preserve.

18.
arXiv (CS.CV) 2026-06-19

Pixel-Level Residual Diffusion Transformer: Scalable 3D CT Volume Generation

Generating high-resolution 3D CT volumes with fine details remains challenging due to substantial computational demands and optimization difficulties inherent to existing generative models. In this paper, we propose the Pixel-Level Residual Diffusion Transformer (PRDiT), a scalable generative framework that synthesizes high-quality 3D medical volumes directly at voxel-level. PRDiT introduces a two-stage training architecture comprising 1) a local denoiser in the form of an MLP-based blind estimator operating on overlapping 3D patches to separate low-frequency structures efficiently, and 2) a global residual diffusion transformer employing memory-efficient attention to model and refine high-frequency residuals across entire volumes. This coarse-to-fine modeling strategy simplifies optimization, enhances training stability, and effectively preserves subtle structures without the limitations of an autoencoder bottleneck. Extensive experiments conducted on the LIDC-IDRI and RAD-ChestCT datasets demonstrate that PRDiT consistently outperforms state-of-the-art models, such as HA-GAN, 3D LDM and WDM-3D, achieving significantly lower 3D FID, MMD and Wasserstein distance scores.

19.
arXiv (CS.LG) 2026-06-15

Testing For Distribution Shifts with Conditional Conformal Test Martingales

arXiv:2602.13848v2 Announce Type: replace Abstract: We propose a sequential test for detecting arbitrary distribution shifts that allows conformal test martingales (CTMs) to work under a fixed, reference-conditional setting. Existing CTM detectors construct test martingales by continually growing a reference set with each incoming sample, using it to assess how atypical the new sample is relative to past observations. While this design yields anytime-valid type-I error control, it suffers from test-time contamination: after a change, post-shift observations enter the reference set and dilute the evidence for distribution shift, increasing detection delay and reducing power. In contrast, our method avoids contamination by design by comparing each new sample to a fixed null reference dataset. Our main technical contribution is a robust martingale construction that remains valid conditional on the null reference data, achieved by explicitly accounting for the estimation error in the reference distribution induced by the finite reference set. This yields anytime-valid type-I error control together with guarantees of asymptotic power one and bounded expected detection delay. Empirically, our method detects shifts faster than standard CTMs, providing a powerful and reliable distribution-shift detector.

20.
arXiv (CS.CV) 2026-06-16

Dynamic Black-hole Emission Tomography with Physics-informed Neural Fields

With the success of static black-hole imaging, the next frontier is the dynamic and 3D imaging of black holes. Recovering the dynamic 3D gas near a black hole would reveal previously-unseen parts of the universe and inform new physics models. However, only sparse radio measurements from a single viewpoint are possible, making the dynamic 3D reconstruction problem significantly ill-posed. Previously, BH-NeRF addressed the ill-posed problem by assuming Keplerian dynamics of the gas, but this assumption breaks down near the black hole, where the strong gravitational pull of the black hole and increased electromagnetic activity complicate fluid dynamics. To overcome the restrictive assumptions of BH-NeRF, we propose PI-DEF, a physics-informed approach that uses differentiable neural rendering to fit a 4D (time + 3D) emissivity field given EHT measurements. Our approach jointly reconstructs the 3D velocity field with the 4D emissivity field and enforces the velocity as a soft constraint on the dynamics of the emissivity. In experiments on simulated data, we find significantly improved reconstruction accuracy over both BH-NeRF and a physics-agnostic approach. We demonstrate how our method may be used to estimate other physics parameters of the black hole, such as its spin.

21.
arXiv (CS.LG) 2026-06-18

Beyond Algorithms: Conceptual Innovation in Medical Imaging AI

arXiv:2606.19270v1 Announce Type: cross Abstract: Artificial intelligence has driven rapid progress in medical imaging research, producing increasingly sophisticated algorithms and steady improvements on benchmark tasks. However, this algorithm-centric trajectory has also revealed a growing imbalance: while computational methods advance rapidly, the conceptual foundations that define imaging tasks, evaluation metrics, and clinical meaning sometimes remain underexamined. In this Perspective, we distinguish algorithmic innovation, which focuses on improving computational implementations and performance within a fixed problem definition, from conceptual innovation, which reframes what problems are posed, how success is measured, and why an approach is clinically relevant. We argue that prevailing incentive structures, training pathways, and publication norms disproportionately reward algorithmic novelty, particularly for early-career researchers, while at times undervaluing conceptual contributions that are essential for scientific maturation and clinical translation. Through representative examples from medical imaging AI, we show how insufficient conceptual grounding can lead to misaligned objectives, fragile generalization, and limited real-world impact. We conclude with actionable recommendations for researchers, mentors, reviewers, and journals to better recognize, support, and integrate conceptual innovation alongside algorithmic advances.

22.
arXiv (CS.LG) 2026-06-15

PepALD: Macrocyclic Peptide Generation via Autoregressive Latent Diffusion

arXiv:2606.14510v1 Announce Type: new Abstract: Macrocyclic peptides are promising therapeutic candidates for intracellular targets, but their design requires simultaneous control over non-natural monomer chemistry, ring topology, membrane permeability, and target binding. Existing SMILES- or HELM-string generative models either operate in long atom-level sequence spaces or treat monomers as symbolic tokens with limited chemical grounding. We introduce PepALD, an Autoregressive Latent Diffusion (ALD) foundation model for de novo macrocyclic peptide generation. The model represents HELM monomers with structured chemical embeddings, generates each residue through context-conditioned diffusion in chemically informed latent space, predicts R-group-aware ring closures during autoregressive generation, and aligns the denoiser to affinity rewards using winner-protected diffusion-adapted preference optimization. In silico experiments demonstrate PepALD's generation quality and reward-optimization performance against representative peptide generation baselines.

23.
arXiv (CS.LG) 2026-06-18

Unraveling the Mechanism of Drug Binding to SARS-CoV-2 RNA Pseudoknot with Thermodynamics-Driven Machine Learning

arXiv:2604.14906v3 Announce Type: replace-cross Abstract: The pseudoknot secondary structure in SARS-CoV-2 RNA is essential for regulating protein synthesis through $-$1 programmed ribosomal frameshifting ($-1$ PRF), a mechanism that allows the virus to generate both structural and non-structural proteins from overlapping reading frames. This pseudoknot exhibits both threaded and unthreaded long-lived topologies. The influence of ligand binding on its folding is a process critical for the development of $-$1 PRF small-molecule inhibitors. Understanding this process through unbiased molecular dynamics (MD) simulations can be facilitated by introducing collective variables (CVs) that capture the corresponding slowest dynamical modes. Here, we use spectral map (SM), a thermodynamics-driven machine learning technique, to learn such CVs directly from all-atom MD trajectories of the SARS-CoV-2 RNA pseudoknot in complex with the $-$1 PRF inhibitor merafloxacin and its two structural analogs in neutral and ionized forms. Free-energy landscapes (FELs) derived from the learned CVs indicate that ligand-induced destabilization is topology-selective. In the threaded pseudoknot, the inhibitors destabilize the S2 stem, while in the unthreaded pseudoknot, destabilization occurs in the S1 and S3 stems. Furthermore, the extent to which each ligand reshapes the FEL matches experimentally reported antiviral potency, whereas the protonation state qualitatively alters dynamics within the same RNA topology. Overall, our results show how pseudoknot topology, ligand type, and protonation state collectively influence the slow conformational dynamics of viral RNA and establish physiological protonation as a critical factor for modeling RNA-targeted drug action.

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

Input-Dependent Fisher Information for Local Sensitivity Analysis of Medical Image Classifiers

arXiv:2606.16362v1 Announce Type: cross Abstract: Deep neural networks have achieved strong performance in medical image classification, but often work like black-box. Commonly used post-hoc interpretation methods often provide heuristic visualizations whose relationship to the classifier's predictive distribution is indirect. This work introduces a local sensitivity analysis framework based on the input-dependent Fisher Information Matrix (iFIM) of a trained classifier. The iFIM characterizes how the classifier's predictive distribution changes under infinitesimal perturbations of the input image. By using a Gram-matrix formulation, the nonzero eigenspectrum of the iFIM can be recovered without explicitly forming the full image-dimensional Fisher matrix. The leading iFIM eigenspace is then used to project an input image into a high local-sensitivity component and its orthogonal component. These components provide a model-intrinsic description of local predictive sensitivity, rather than a conventional pixel-wise attribution heatmap or a causal segmentation of task-relevant anatomy. The framework is evaluated on controlled and clinical medical image classification tasks using multiple classifier architectures. Perturbation-based experiments show that high-sensitivity iFIM components are more strongly coupled to changes in predictive confidence and classification performance than lower-sensitivity complementary components. The results support the iFIM framework as a principled tool for analyzing local decision sensitivity and for complementing existing attribution-based interpretability methods in medical imaging.

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

A Recipe for Long-Context Reasoning in Large Language Models via On-Policy Optimization and Distillation

Existing approaches to post-train models for long-context tasks face complementary limitations: (i) supervised fine-tuning (SFT) provides stable supervision but suffers from exposure bias; (ii) reinforcement learning methods such as Group Relative Policy Optimization (GRPO) train on model-generated trajectories but struggle with long-horizon credit assignment and sparse rewards; and (iii) on-policy distillation (OPD) provides dense token-level guidance but does not directly optimize task rewards. We study these complementary strategies for long-context alignment and derive a recipe that combines GRPO with OPD-style teacher guidance: the student learns from its own rollouts using outcome-level rewards, while a stronger teacher provides dense token-level regularization in place of the standard reference policy. This is especially useful when process-level supervision is difficult to obtain. To support this study, we introduce LongBlocks, a synthetic multilingual dataset spanning multi-hop reasoning, contextual grounding, and long-form generation. Through controlled ablations, we isolate the roles of cold-start initialization, teacher anchoring, and data mixing, showing that our recipe yields a more stable and effective path to long-context reasoning than GRPO or OPD while preserving short-context capabilities.