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01.
medRxiv (Medicine) 2026-06-11

Development of iADJUST: a theory-informed, patient co-designed digital psychological intervention for adjustment in chronic kidney disease

Background: Psychological distress is common in chronic kidney disease (CKD) and is associated with reduced quality of life, treatment non-adherence, and worse clinical outcomes. Distress in CKD is also linked to difficulties adjusting to the demands of illness management. Despite this, psychological support remains inconsistently integrated within kidney care pathways, and existing interventions often lack clear theoretical specification and explicit targeting of mechanisms underpinning adjustment to CKD. Objectives: To describe the systematic development of iADJUST, a theory-informed patient co-designed digital psychological intervention targeting key cognitive and behavioural mechanisms involved in adjustment to CKD. Methods: Intervention development was guided by the Medical Research Council framework for complex interventions. A structured, iterative process integrated empirical evidence, psychological theory, and patient and public involvement and engagement. The Common-Sense Model of Self-Regulation and cognitive behavioural theories informed the identification of modifiable maintaining mechanisms associated with adjustment to CKD. Intervention components were mapped onto these mechanisms and refined through co-design with people living with CKD. Results: iADJUST is a six-session self-guided digital psychological intervention delivered over 12 weeks and supplemented by therapist contact. The intervention targets illness-related uncertainty, fatigue-related activity dysregulation, catastrophic what-if thinking, self-critical evaluation, and behavioural withdrawal. It integrates psychoeducation, cognitive and behavioural strategies, maintenance planning, and elements from acceptance and commitment therapy and compassion-focused approaches. Content is delivered through video, audio, and guided tasks and activities. Conclusion: iADJUST provides a theory-informed, evidence-based psychological intervention for CKD explicitly mapping intervention components to maintaining cognitive and behavioural mechanisms implicated in adjustment. Feasibility evaluation is underway.

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

Do Large Language Models Have Emotions?

arXiv:2606.14742v1 Announce Type: cross Abstract: Do LLMs have emotions? A recent paper from Anthropic reports finding internal representations of emotion concepts in Claude Sonnet 4.5, concluding that the LLM has 'functional emotions.' We evaluate this claim against what is known about how emotions actually function in biological systems. We argue that emotions serve two core functions: the context-sensitive interpretation of situations, and the reorganization of processing across multiple systems in response to those interpretations. The Anthropic findings offer partial support for the first function, though the consistent, discrete emotional representations identified in Claude sit uneasily with affective neuroscience findings that human emotion is characterized by variable rather than uniform neural signatures. On the second function, the evidence is mixed: Claude's representations modulate output without producing the dynamic reorganization of attention, decision speed, and motivational state that defines emotion in biological systems. We close by proposing what it would take for an LLM to have emotions.

03.
arXiv (CS.AI) 2026-06-11

Market Design for AI: Beyond the Copyright Binary

arXiv:2606.12260v1 Announce Type: cross Abstract: How can we design a market of human-generated content for use in training AI models that both enables technological progress and preserves individual incentives for high-quality content creation? Existing approaches take polar positions: a "free-for-all" model based on fair use and a "strong intellectual property rights" model. We show that both fail: Free-for-all does not compensate creators, and – by modeling as a static Stackelberg game – strong intellectual property rights also underpower creative incentives. We find this especially true for more innovative creators, a phenomenon we term the "originality penalty." Extending this insight to a dynamic model, we find another market failure undermining AI model performance, even for an initially good model: Such a model induces greater reliance by humans on AI-assisted creation, resulting in homogenized content feeding back into training, which degrades the model performance – a "curse of precision." We further propose a market design with a data intermediary internalizing cross-creator externalities and subsidizing innovative contributions, thereby restoring efficiency.

04.
arXiv (CS.AI) 2026-06-15

HierSVA: A Data Synthesis Pipeline, Dataset, and Benchmark for LLM-Driven Hierarchical Hardware Formal Verification

arXiv:2606.13706v1 Announce Type: cross Abstract: We present HierSVA, an integrated suite that combines a pipeline, dataset, and benchmark for LLM-driven hierarchical hardware formal verification. HierSVA-SP pairs an RTL preprocessing toolchain with an LLM-in-the-loop formal verification flow to produce reference SystemVerilog Assertions (SVA) on hierarchical RTL. Applying it to BaseJump STL yields HierSVA-DS, a dataset of 342 modules, with hierarchy metadata and depths 0–9, accompanied by a deep subset of 28 module-bug pairs with natural-language specifications and bug variants. HierSVA-B decomposes assertion quality into six metric axes: syntax correctness, assertion proof success rate, vacuity, specification faithfulness, mutation coverage, and formal core coverage. Applying HierSVA-B to twelve recent LLMs reveals three findings. First, the module-level compile rate is 67.1\%; among generated assertions in evaluable runs, 82.1\% prove non-vacuously, but the corresponding assertion sets detect only 70.2\% of eligible injected faults and cover 36.2\% of the formal core. Second, on 211 evaluable model–module entries in the deep subset, assertion sets flag buggy RTL with 0.87 recall, but 40\% of predicted-buggy outcomes are false positives on correct RTL, limiting precision to 0.60. Third, agentic mode improves S1-style provability and strength metrics, but gains plateau and oscillate. Codes and artifacts are available at \href{https://github.com/HierSVAAnon/HierSVACodeAndArtifacts}{https://github.com/HierSVAAnon/HierSVACodeAndArtifacts}. Dataset is available at \href{https://huggingface.co/datasets/AnonymousHierSVA/HierSVA}{https://huggingface.co/datasets/AnonymousHierSVA/HierSVA}.

05.
arXiv (CS.CL) 2026-06-16

Emergent retokenization symmetry in large language models: phenomenology and applications

Tokenization introduces representational redundancy: under a fixed token vocabulary, every byte string admits many valid token encodings, or segmentations, that decode to the same surface string. However, given a prompt, most language model tokenizers break this representational symmetry by returning a canonical segmentation. Training only on canonical segmentations should influence inference behavior, and there is little reason to expect models to respect segmentation symmetry on downstream tasks. We find that this symmetry partially emerges during training. Here, we probe this emergent symmetry through experiments testing token compositional understanding, representation diversity, and task focused benchmark performance. We primarily use retokenization – replacing a prompt's canonical tokenization with an alternative segmentation while preserving its bytes exactly. Relative to other prompt perturbations, retokenization is unusually clean because it isolates segmentation effects without changing syntax, semantics or surface form. We use retokenization to study sensitivity and robustness to semantically identical input representations across pretraining and post-training. Moreover, this partial retokenization symmetry suggests a distinct inference-time sampling axis. While temperature sampling generates diverse outputs from the model using its next-token probability distribution, retokenization generates diversity from the model's internal computations through semantically equivalent input representations. We find that while this retokenization sampling strategy can hurt performance on easy problems, it can also recover solutions that conventional sampling does not find. Overall, our work presents retokenization as a simple yet powerful probe of large language models, shedding light on compositional understanding and prompt sensitivity, and offering a novel sampling strategy.

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

From Seeing to Experiencing: Scaling Navigation Foundation Models with Reinforcement Learning

Navigation foundation models trained on massive web-scale data enable agents to generalize across diverse environments and embodiments. However, these models, which are trained solely on offline data, often lack the capacity to reason about the consequences of their actions or adapt through counterfactual understanding. They thus face significant limitations in real-world urban navigation, where interactive and safe behaviors, such as avoiding obstacles and moving pedestrians, are critical. To tackle these challenges, we introduce the Seeing-to-Experiencing (S2E) learning framework to scale the capability of navigation foundation models with reinforcement learning. S2E combines the strengths of pretraining on offline videos and post-training through reinforcement learning. It maintains the model's generalizability acquired from large-scale real-world videos while enhancing its interactivity through reinforcement learning in simulation environments. Specifically, we introduce two innovations: (1) an Anchor-Guided Distribution Matching strategy for offline pretraining, which stabilizes learning and models diverse motion patterns through anchor-based supervision; and (2) a Residual-Attention Module for reinforcement learning, which obtains reactive behaviors from simulation environments without erasing the model's pretrained knowledge. Moreover, we establish a comprehensive end-to-end evaluation benchmark, NavBench-GS, built on photorealistic 3D Gaussian Splatting reconstructions of real-world scenes that incorporate physical interactions. It can systematically assess the generalizability and safety of navigation foundation models.

07.
arXiv (CS.LG) 2026-06-19

A High-Resolution Landscape Dataset for Concept-Based XAI With Application to Species Distribution Models

arXiv:2604.13240v2 Announce Type: replace-cross Abstract: Mapping the spatial distribution of species is essential for conservation policy and invasive species management. Species distribution models (SDMs) are the primary tools for this task, serving two purposes: achieving robust predictive performance while providing ecological insights into the driving factors of distribution. However, the increasing complexity of deep learning SDMs has made extracting these insights more challenging. To reconcile these objectives, we propose the first implementation of concept-based Explainable AI (XAI) for SDMs. We leverage the Robust TCAV (Testing with Concept Activation Vectors) methodology to quantify the influence of landscape concepts on model predictions. To enable this, we provide a new open-access landscape concept dataset derived from high-resolution multispectral and LiDAR drone imagery. It includes 653 patches across 15 distinct landscape concepts and 1,450 random reference patches, designed to suit a wide range of species. We demonstrate this approach through a case study of two aquatic insects, Plecoptera and Trichoptera, using two Convolutional Neural Networks and one Vision Transformer. Results show that concept-based XAI helps validate SDMs against expert knowledge while uncovering novel associations that generate new ecological hypotheses. Robust TCAV also provides landscape-level information, useful for policy-making and land management. Code and datasets are publicly available.

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

Evaluating and Enhancing Negation Comprehension in Remote Sensing MLLMs

arXiv:2606.20177v1 Announce Type: cross Abstract: Multimodal Large Language Models (MLLMs) have demonstrated remarkable success in various Remote Sensing (RS) tasks. However, their ability to comprehend negation remains underexplored, limiting deployment in real-world applications where models must explicitly identify what is false or absent, e.g., emergency responders need to locate non-flooded routes for evacuation. To comprehensively study this limitation, we introduce RS-Neg, the first benchmark to evaluate negation understanding across region-level to scene-level tasks. Specifically, we design an automated data generation pipeline for RS imagery, using LLMs to synthesize diverse negation queries, and introduce a dynamic visual focus module for verification. Our evaluation reveals that advanced RS MLLMs struggle with negation, exhibiting hallucinations and substantial performance degradation. To close this gap, we propose NeFo, a novel test-time learning method that explicitly incorporates the logical role of negation into the model optimization. Remarkably, using about 5\% unlabeled test samples, NeFo significantly improves the negation understanding of models and shows strong generalization to unseen tasks. Code and data will be released upon acceptance.

09.
arXiv (quant-ph) 2026-06-15

On-site interactions in quantum thermal machines: efficiency, rectification and entanglement beyond local and global master equations

arXiv:2606.14593v1 Announce Type: new Abstract: Advances in experimental techniques have opened new routes for harnessing non-equilibrium dynamics in mesoscopic quantum systems. In this context, we study the impact of on-site interactions on the transport properties of a continuous quantum thermal machine composed of two coupled oscillators connected to two thermal reservoirs. In the weak system-reservoir coupling regime, where a long-standing debate concerns which reduced description should be preferred, we first show that the Redfield master equation (RME) provides an accurate and unifying framework that interpolates between two well-known limits: the local and global master equations. By relying on the Hierarchy of Pure States (HOPS), a numerically exact stochastic method, we then explore the full parameter space and show that interactions can be leveraged to tune the efficiency of the thermal machine at high temperatures (while leaving it essentially unchanged at low temperatures), induce non-reciprocal transport under asymmetric reservoir couplings, and generate steady-state entanglement within the junction. We derive expressions for system-bath correlators, such as heat and particle currents, consistently across different frameworks. Our work features on-site interactions to enhance the versatility of quantum thermodynamic junctions and clarifies the role of non-Markovianity and non-linearities in quantum transport.

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

Track2View: 4D-Consistent Camera-Controlled Video Generation via Paired 3D Point Tracks

Re-rendering an existing video from a novel camera viewpoint requires the output to follow the prescribed camera trajectory while preserving the appearance and dynamics of the original scene across every frame. Existing methods rely on per-frame pose embeddings, noisy point-cloud renderings, or implicit learned correspondences, none of which provides an explicit, temporally continuous link between source and target pixels. We propose Track2View, which conditions a video diffusion transformer on paired 3D point tracks: sparse trajectories of scene points projected into both the source and target camera views. These tracks provide explicit spatiotemporal correspondences that are temporally continuous by construction, encoding what content should appear where and when. At the core of Track2View is a dual-view track conditioner that transfers visual context from source to target view through parameter-free geometric operations and learned temporal aggregation, ensuring generalization to arbitrary camera trajectories without memorizing specific motions. We further introduce a data curation pipeline that extracts one-to-one track correspondences by running a 3D point tracker on temporally concatenated multi-camera view pairs. On a 400-video benchmark spanning static and dynamic scenes, Track2View achieves state-of-the-art results across visual quality, view synchronization, and camera accuracy, reducing rotation error by 30-65% and translation error by 61-72% relative to leading baselines. Project page is available at this https URL: https://qjizhi.github.io/track2view

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

Conservation Laws for Modern Neural Architectures

arXiv:2606.17816v1 Announce Type: cross Abstract: Understanding gradient descent dynamics is key to explaining the success of over-parameterized models, where implicit bias manifests through conservation laws in gradient flow. While such laws are well understood for linear and ReLU networks, they remain largely unexplored for modern architectures. This work develops a unified framework to characterize conservation laws for contemporary models, including feedforward networks with GELU, SiLU, and SwiGLU activations, multihead attention with sinusoidal and rotary positional encodings, and Mixture-of-Experts architectures under diverse gating designs. Our theoretical findings are supported by experiments that validate the predicted invariants.

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

Time-Conditioned and Multi-Time Survival Prediction from 2D PET/CT Projections in Lung Cancer

Accurate prediction of overall survival (OS) from positron emission tomography/computed tomography (PET/CT) can support personalized treatment and follow-up strategies in oncology. However, the impact of temporal modeling on imaging-based survival prediction remains insufficiently explored. We investigate how different temporal formulations influence survival prediction by developing two complementary approaches: Attention-guided Time-Conditioned Survival (ATCS) and Multi-Time Survival (MTS). We retrospectively analyzed pre-treatment PET/CT images from 848 patients with non-small cell lung cancer (NSCLC), including 556 for model development and 292 for held-out testing. A previously proposed Time-Conditioned Survival (TCS) model was used as a baseline. Models were trained using 5-fold cross-validation and evaluated on the test set using time-dependent area under the curve (AUC) at 6-month intervals from 0.5 to 5 years. Both ATCS and MTS outperformed the baseline TCS model, achieving mean AUCs of 0.794 and 0.793, respectively, compared to 0.767. ATCS performed better at earlier time points (0.5-3 years), whereas MTS performed better at later intervals (3.5-5 years). Combining tumor-specific and tissue-wise PET/CT features improved performance over either input alone. Finer temporal discretization improved short-term prediction, while coarser intervals provided more stable long-term estimates. These findings demonstrate that temporal modeling and input design influence PET/CT-based survival prediction. The proposed approaches enable time-specific survival estimation from pre-treatment imaging and may support improved risk stratification and clinical decision-making.

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

Self-Evolving Multi-Agent Systems via Textual Backpropagation

arXiv:2506.09046v3 Announce Type: replace-cross Abstract: Leveraging multiple Large Language Models (LLMs) has proven effective for addressing complex, high-dimensional tasks, but current approaches often rely on static, manually engineered multi-agent configurations. To overcome these constraints, we present the Agentic Neural Network (ANN), a framework that conceptualizes multi-agent collaboration as a layered neural network architecture. In this design, each agent operates as a node, and each layer forms a cooperative team focused on a specific subtask. Our framework follows a two-phase optimization strategy: (1) Forward Phase - Drawing inspiration from neural network forward passes, tasks are dynamically decomposed into subtasks, and cooperative agent teams with suitable aggregation methods are constructed layer by layer. (2) Backward Phase - Mirroring backpropagation, we refine both global and local collaboration through iterative feedback, allowing agents to self-evolve their roles, prompts, and coordination. This neuro-symbolic approach enables our framework to create new or specialized agent teams post-training, delivering notable gains in accuracy and adaptability. Across seven benchmark datasets, our work surpasses leading multi-agent baselines under the same configurations, showing consistent performance improvements.

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

PolyFlow: Safe and Efficient Polytope-Constrained Flow Matching with Constraint Embedding and Projection-free Update

arXiv:2606.13400v1 Announce Type: cross Abstract: While flow-based generative models have demonstrated strong performance across a wide range of domains, deploying them in safety-critical physical systems remains challenging due to strict constraint requirements. Existing approaches typically enforce safety through post-hoc corrections, which incur substantial computational overhead and may distort the learned distribution. We propose PolyFlow, a polytope-constrained flow matching framework that embeds constraints directly into the model and flow dynamics. PolyFlow introduces a discrete-time flow formulation and a projection-free architecture, which eliminate the discretization error and guarantee strict satisfaction of arbitrary polyhedral constraints, without the need for expensive iterative solvers. Experimental results show that PolyFlow achieves zero constraint violation while maintaining high distributional fidelity across a range of planning and control tasks. Compared to state-of-the-art constrained generation baselines, PolyFlow significantly reduces inference latency and demonstrates a favorable trade-off between safety, efficiency, and generative quality. Code is available on https://github.com/MJianM/PolyFlow.

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

MedRLM: Recursive Multimodal Health Intelligence for Long-Context Clinical Reasoning, Sensor-Guided Screening, Evidence-Grounded Decision Support, and Community-to-Tertiary Referral Optimization

Real-world clinical decision support requires reasoning over heterogeneous and longitudinal patient information rather than answering isolated medical questions. However, current medical large language models and retrieval-augmented generation systems often rely on single-step prompting or retrieval, which can be fragile when clinical evidence is distributed across long electronic health records, medical images, sensor streams, guidelines, and referral constraints. This paper proposes MedRLM, a Recursive Multimodal Health Intelligence framework for long-context clinical reasoning, sensor-guided screening, and community-to-tertiary referral support. Instead of compressing all patient information into one prompt, MedRLM treats the patient case as an external clinical environment that can be recursively inspected, decomposed, retrieved, verified, and synthesized. The framework coordinates specialized agents for clinical text, longitudinal EHR, medical imaging, physiological sensor signals, guideline retrieval, uncertainty auditing, and referral planning. It further introduces a Clinical Evidence Graph Memory to connect patient-specific observations with retrieved evidence, standardized definitions, sensor-derived biomarkers, and referral criteria. A sensor-guided recursive triggering mechanism activates deeper reasoning when abnormal physiological or behavioral patterns are detected, while uncertainty-gated refinement supports clinician review for high-risk or low-confidence cases. We also outline a real-data evaluation design using public and credentialed clinical datasets spanning EHR, radiology, ECG, ICU time series, and referral-proxy outcomes. MedRLM aims to move medical AI from static question answering toward auditable, multimodal, and workflow-aware clinical decision support.

16.
arXiv (quant-ph) 2026-06-15

Emission of time-ordered photon pairs from a coherently-driven Kerr microcavity

arXiv:2601.06468v2 Announce Type: replace-cross Abstract: Weakly-interacting many-body systems possess remarkable quantum properties that are essential components of quantum technologies, and constitute a topic of fundamental interest. Here we show that in a solid-state nonlinear microcavity embedding discrete modes of exciton-dressed photons, we can isolate a single eigenmode of quantum fluctuations from the much brighter coherent fraction of the field. In this regime, we perform frequency- and time-resolved correlations measurements between photons on the red and blue side of the fluctuations spectrum. When the average number of fluctuation quanta is smaller than one, we observe the formation of large pairwise time-ordered correlations: red photon first and blue photon second. We show that this peculiar time-ordering correlation emerges spontaneously from the interplay between frequency-resolved detection, and the non-trivial internal quantum structure of the elementary fluctuations.

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

ReA-OVCD: Reliability-Aware Open-Vocabulary Change Detection via Semantic and Spatial Refinement

Unlike traditional remote sensing change detection that relies on predefined categories, Open-Vocabulary Change Detection (OVCD) identifies land cover changes flexibly using arbitrary text prompts. However, existing methods suffer from an inherent trade-off when modeling changes: instance-level comparison overlooks fine-grained semantic variations (e.g., partial building extensions), while direct pixel comparison proves unreliable, yielding unstable responses and boundary artifacts due to semantic ambiguity and spatial inconsistency. To this end, we propose an efficient training-free Reliability-Aware Open-Vocabulary Change Detection (ReA-OVCD) framework. It first derives candidate change regions from pixel-wise semantic discrepancies to ensure flexible and detailed localization. To ensure reliability, it subsequently introduces a collaborative refinement strategy to explicitly model change validity from both semantic and spatial perspectives. Specifically, we develop a Semantic Change Reasoning (SCR) module that reassesses changes by jointly analyzing distributional divergence and response variation, enabling the suppression of incidental inconsistencies while preserving reliable semantic shifts. In addition, a Boundary-aware Change Refinement (BCR) module is designed to mitigate artifacts stemming from boundary misalignment and uncertainty through validating whether candidate regions are supported by reliable interior pixels. Extensive experiments across multiple datasets (LEVIR-CD, WHU-CD, DSIFN, and SECOND) demonstrate that our method consistently outperforms state-of-the-art approaches, achieving $\mathrm{F}_{1}^{C}$ improvements of 2.13\% to 9.75\% with higher computational efficiency. The code is publicly available at \https://github.com/Funny0101/ReA-OVCD

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

Visual-Seeker: Towards Visual-Native Multimodal Agentic Search via Active Visual Reasoning

arXiv:2606.15231v1 Announce Type: new Abstract: Multimodal large language models (MLLMs) have demonstrated impressive capabilities in many visual tasks, but they often struggle with factual grounding when confronted with complex, open-world scenarios. While recent multimodal deep search agents attempt to address this issue by utilizing external tools, the visual-native search paradigm remains underexplored. Existing methods primarily rely on simple images with explicit semantics and text-only evidence trajectories, limiting the agent's ability to perform multi-hop, cross-modal reasoning and search. To address these limitations, we propose Visual-Seeker, a visual-native multimodal deep search agent via active visual reasoning. Rather than treating vision as a static input, our agent actively attends to fine-grained visual details, dynamically harvests visual evidence throughout the search process. To unlock its visual-native potential, we design an active visual reasoning data pipeline and synthesize 5K high-quality multimodal trajectories for model training. Extensive experiments demonstrate the state-of-the-art performance across five challenging multimodal search benchmarks, even surpassing several proprietary models, validating robust visual-native reasoning and search in real-world web environments. The code and data can be accessed at: https://github.com/ZhengboZhang/Visual-Seeker.

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

Understanding Diversity Collapse in RLVR via the Lens of Overtraining

arXiv:2606.15455v1 Announce Type: cross Abstract: Reinforcement learning with verifiable rewards (RLVR) has become a key approach for enhancing the reasoning abilities of large language models. However, RLVR often suffers from diversity collapse: Pass@$1$ improves while high-$k$ Pass@$k$ degrades, which is viewed as a narrowing of the model's reasoning boundary. We formalize this diversity collapse through the lens of overtraining: once a problem's contribution to the reference metric has effectively saturated, further updates no longer expand what the model can solve but still concentrate probability mass on the trajectories favored by on-policy sampling. Under a standard setup with few rollouts per problem, even a single observed success places a problem in a nearly saturated regime for high-$k$ Pass@$k$, so most updates in standard RLVR are overtraining from the boundary perspective. This perspective also suggests a reading of whether RLVR can expand the model's reasoning abilities beyond the base model: since RLVR is structurally biased against high-$k$ Pass@$k$, its aggregate decline does not by itself mean that no new reasoning gains occurred. Interventionally, restricting updates to problems with zero observed success lifts Pass@$256$ above the base model on difficult benchmarks; observationally, a non-trivial fraction of initially unsolvable problems become solvable during standard RLVR training. Building on these findings, we propose Bayesian Boundary Gating (BBG), which redirects optimization away from overtraining by estimating each problem's marginal contribution to the reasoning boundary. Across multiple reasoning benchmarks, BBG improves average Pass@$k$ across a wide range of $k$.

20.
medRxiv (Medicine) 2026-06-17

What Urine Measures Is Not What Tissue Encodes: Compartment-Specific miRNA Coordination in Prostate Cancer

Abstract Background Prostate cancer (PCa) diagnosis remains challenged by the limited specificity of prostate-specific antigen (PSA) testing, which cannot reliably distinguish malignancy from benign prostatic hyperplasia (BPH). MicroRNAs (miRNAs) are emerging candidates for liquid biopsy-based diagnostics, but most studies assess expression in isolation within a single compartment (biological source - Tissue, blood, serum, urine etc.), overlooking both compartment-specific behavior and the coordinated relationships among miRNAs. Methods We profiled four candidate miRNAs — miR-19b-3p, miR-21-5p, miR-101-3p and miR-375-3p, across four biological compartments (prostate tumor tissue, urine, serum, and blood) in 179 patients undergoing prostate biopsy for clinical suspicion of PCa (104 PCa, 75 BPH) using qRT-PCR. Urinary exosomal RNA was isolated with a commercial exosome isolation kit so from here onwards this compartment will be referred to as urine. Differential expression was quantified using Cohen's d; inter-miRNA coordination was assessed via Spearman correlation and differential correlation ({delta} r) analysis; and a compartment-level network rewiring score was derived as the sum of {delta} r| across miRNA pairs. Cross-compartment structural alignment was evaluated by comparing correlation patterns at the population level. Diagnostic models combining PSA, age, and urinary exosomal-miRNA features were evaluated using Logistic Regression, Elastic Net Logistic Regression and Naive Bayes classifiers under leave-one-out cross-validation (LOOCV). Results Effect sizes were largest and most consistent in urine, with miR-101-3p showing the strongest separation between PCa and BPH (d = -1.01), followed by miR-21-5p (d {approx}-0.72$) and miR-19b-3p (d {approx}-0.64). Two markers (miR-19b-3p, miR-375-3p) showed directional reversals across compartments, indicating that disease-associated signals are compartment-specific rather than uniformly conserved. In tumor tissue, PCa was associated with substantial reorganization of inter-miRNA coordination (network rewiring score = 2.46), including the emergence of a strong miR-21-5p–miR-375-3p co-regulatory axis ({delta} r = +0.87$) and decoupling of the miR-21-5p–miR-19b-3p relationship ({delta}r = -0.64$). Urine showed a structurally distinct coordination pattern (rewiring score = 1.77), dominated by a miR-101-3p–miR-19b-3p axis (r = +0.56) absent from tissue; cross-compartment comparison showed concordance in only 1 of 5 miRNA pairs, indicating that urine's architecture is largely independent of tissue's. For diagnostic translation, the conventional PSA cutoff (4 ng/mL) achieved 100% sensitivity but only 23.5% specificity. In urine, miR-101-3p performs better than other miRNAs, with AUC of 0.77 (95% CI: 0.62–0.90). Adding PSA and age to the urinary miR-101-3p further improved discrimination to an AUC of 0.91 (95% CI: 0.82–0.99), with 70% specificity at 92% sensitivity; this pattern was consistent across Elastic Net and Logistic Regression classifiers. Expanding the model to include all urinary miRNAs, age, and pair-derived coordination features did not improve on this result (AUC = 0.88), indicating that population-level coordination changes did not translate into additional individual-level diagnostic value in this cohort. Conclusions miRNA signals in extracellular compartments do not represent direct surrogates of tumor-level molecular architecture; each compartment harbors a distinct, transformed coordination structure reflecting its biological context. While these coordination-level changes are mechanistically informative, the most direct translational gain in this study came from a parsimonious model combining PSA, age with a single urinary marker, miR-101-3p, which improved AUC from 0.77 to 0.91, with specificity 70.5% at 90% sensitivity criteria. This combination represents a promising, interpretable candidate for reducing unnecessary prostate biopsies, pending validation in larger, independent cohorts. Keywords: MicroRNA, Compartment-Specific Biomarkers, Urinary Exosomes, Differential Correlation, Liquid Biopsy, Machine learning, PSA, Early diagnosis

21.
arXiv (CS.CV) 2026-06-16

To forget is to preserve: Machine Unlearning for 3D medical image segmentation

With new data privacy laws such as the General Data Protection Regulation (GDPR) [1] that allow individuals to ask that any of their personal information be erased from trained machine learning models, there has been a push to investigate the unlearning of data from models as a way to comply with these laws. In this regard, based on four mechanics, we consider several approximate unlearning strategies applied to the MRBrainS18 dataset [2]. We use a 3D ResNet-50 [3] as a backbone architecture for segmentation that has been pre-trained with the Med3D framework [4]. Considering the pre-trained model as a baseline, we evaluate respective retention accuracy on 2 types of subjects, i.e., retain and forget. We assess these approaches through their Dice similarity coefficient and mean absolute error (MAE) values using two separate training horizons 20 and 50 epochs. The results show that the Noisy Label strategy had the best overall trade-off with a decrease of 93% in the forget set while maintaining 84% accuracy for the retained set after 50 epochs. All other strategies showed extreme levels of forgetting at higher epoch numbers while also demonstrating catastrophic degradation of their retain set performance. The results of this study provide a strict baseline of performance metrics for unlearning on a subject-specific level and provide practitioners with clear criteria for selecting the proper strategies.

22.
medRxiv (Medicine) 2026-06-17

Proteomics Uncovers Cryptic JPH2 Loss in Paediatric Dilated Cardiomyopathy

Despite recent advances in next-generation sequencing, genetic diagnostic rates for dilated cardiomyopathy (DCM) remain low. Among paediatric DCM, causes are often heritable, with a greater frequency of de novo, recessive and syndromic causes of disease. Novel diagnostic methods are therefore required to solve monogenic cases. To assess the value of proteomics as a diagnostic tool for paediatric DCM, we obtained left ventricle myocardial samples from paediatric patients undergoing heart transplantation at the Royal Children's Hospital, Melbourne. We performed genome sequencing and proteomics and leveraged this multi-omics dataset to uncover the molecular cause of disease in a gene elusive proband. The proband carried a heterozygous JPH2 frameshift variant identified on clinical exome sequencing. However, proteomic analysis showed a pronounced downregulation of JPH2, suggestive of biallelic loss-of-function. Closer inspection of the genomic data revealed a large inversion (~8.34 Mb) with a breakpoint falling within intron 5 of JPH2 that displaces the 3'UTR from the coding transcript. The two variants were confirmed to be in trans using long read DNA sequencing, consistent with a diagnosis of JPH2 autosomal recessive DCM. Finally, we applied RNA sequencing with total RNA library preparation to show that transcripts containing a 3'UTR were reduced to ~10% relative to controls. As a proof-of-principle, we present the first reported use of proteomics from explanted cardiac tissue to provide a genetic diagnosis. Our methodology has broad relevance to patients with genetically unsolved Mendelian diseases, who might undergo organ transplantation as part of clinical management.

23.
arXiv (CS.LG) 2026-06-11

Minimal surfaces, Knots, and Neural Networks

arXiv:2605.26234v2 Announce Type: replace-cross Abstract: A recent conjecture by Joel Fine posits a relationship between the coefficients of the HOMFLY polynomial of a knot $K$ in the 3-sphere $S^3$, and the signed count of minimal surfaces in hyperbolic 4-space $\mathrm{H}^4$ meeting the sphere at infinity at $K$, with prescribed genus and self-intersection number. In this paper, we develop a novel machine learning framework based on Physics-Informed Neural Networks (PINNs) to solve the minimal surface equation in hyperbolic space. We utilise this framework to test Fine's Conjecture by constructing near-minimal surfaces bounding various families of knots in $S^3$. Furthermore, we develop an algorithmic method to find self-intersections and compute their sign. For every knot analysed, the computationally discovered minimal surfaces and their self-intersection numbers perfectly align with the predictions of Fine's Conjecture, providing empirical evidence for it.

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

LLM-Assisted Stance Detection in Scientific Discourse: A Test Case in Bayesian Cognitive Science

Qualitative coding is central to social science, but expert annotation is difficult to scale. LLMs offer a possible extension, yet require careful validation when the target construct is interpretive, theoretically loaded, and only indirectly expressed. We study this problem in a difficult case: detecting whether authors treat Bayesian models as descriptions of mental and neural mechanisms (realism) or as useful mathematical tools (instrumentalism). Our method combines a theory-driven codebook, expert-coded reference annotations, a diagnostic-gated prompt-optimization search yielding a shared zero-shot prompt for three frontier LLMs (GPT-5.1, Claude Sonnet 4.6, Gemini 3 Pro Preview), and multi-rater reliability analysis. The final prompt achieved a held-out combined reliability score of 0.76 (harmonic mean of ICC = 0.79 and $\alpha$ = 0.74), with all diagnostics satisfied. Deployed on 6,858 quotes from 210 articles, the three LLMs reached substantial quote-level agreement (ICC = 0.80; $\alpha$ = 0.76; combined = 0.78) and near-perfect article-level rank stability ($r$ = 0.96-0.97 across rater pairs). The corpus was predominantly weakly realist, but article-level stances were rarely uniform: only 1.4% of articles used a single band, while 59.5% spanned four or more. Low-level perception/motor articles scored 8.8 Realism points higher than high-level cognition articles ($p < .001$, $d = 0.60$), quantifying a long-held qualitative intuition. We present this as an expert-led case study; the framework is intended to generalize to similar theoretically demanding tasks, not to all qualitative analysis.

25.
bioRxiv (Bioinfo) 2026-06-11

GermRL: Alleviating The Germline Bias In Autoregressive Antibody Language Models Through Reinforcement Learning

Antibodies are powerful therapeutics whose antigen specificity arises from sequence diversity shaped during development. Recently, language models trained on large antibody repertoire datasets have enabled the generation and screening of novel candidates, but these models retain a strong germline bias. As AI adoption increases in therapeutic workflows, it is crucial to develop models that harness the diversity of antibodies necessary for the discovery of mutations that encode desirable properties. Previous work explored the germline bias in masked antibody language models, yet the bias in generative autoregressive language models has not yet been addressed. Here, we present GermRL, a lightweight and modular reinforcement learning (RL) framework capable of alleviating the germline bias in pre-trained antibody autoregressive language models through group relative policy optimization (GRPO). GermRL achieves consistent one-shot generation of antibodies that satisfy specified mutation thresholds from germline while maintaining structural plausibility. Under the lowest and highest mutation thresholds tested (5 and 35 mutations from germline), GermRL scores 0.992 and 0.950 pass@1, respectively, compared to 0.398 and 0.034 for the pre-trained language model. Within GermRL, we introduce a key pair of modifications to GRPO that increase training efficiency by discouraging reward hacking under our antibody application. Furthermore, comparison of RL generated and natural antibody sequences reveals how RL based optimization can explore alternative evolutionary mutational patterns and residue compositional strategies while preserving key global properties of natural antibodies, including identifiable germline assignments, embedding-level similarity and comparable developability profiles. Thus, RL-trained generative models optimized to promote antibody mutations through diversity from germline provide a promising framework for navigating the antibody sequence landscape, enabling exploration of novel yet biologically plausible candidates for therapeutic design.