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01.
arXiv (CS.CL) 2026-06-15

AgentSpec: Understanding Embodied Agent Scaffolds Through Controlled Composition

LLM agents are increasingly built not as single model calls, but as scaffolded systems that combine reasoning, memory, reflection, action execution, and learning. While such scaffolds often improve performance, they are often embedded in tightly coupled pipelines, making it difficult to isolate component contributions, compare alternative designs, or understand how module interactions shape agent behavior. We introduce AgentSpec, a modular specification framework that represents embodied agents as typed compositions of reusable policy components with standardized interfaces. AgentSpec standardizes the interfaces among perception, memory, reasoning, reflection, action, and optional learning, enabling components to be swapped and recombined under controlled conditions. We instantiate this framework across DeliveryBench, ALFRED, MiniGrid, and RoboTHOR, and analyze reasoning, memory, reflection, and reinforcement-learning modules across model backbones. Our results show that agent performance is governed by scaffold compatibility and interaction effects rather than isolated module strength. In particular, structured multi-granularity memory improves long-horizon state tracking, reasoning and memory interact non-uniformly across environments, reflection trades off correction and cost, and RL-trained policies compose best when optimized with deployment-time scaffold structure. AgentSpec provides a controlled foundation for studying, comparing, and designing composable LLM agents. Our code, baselines and interactive playground are publicly available at https://agentspec-embodied.github.io.

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

DiFlow-TTS: Compact and Low-Latency Zero-Shot Text-to-Speech with Discrete Flow Matching

Zero-shot text-to-speech (TTS) has made significant progress in replicating unseen voices, yet balancing generation quality and inference efficiency remains challenging. Autoregressive models suffer from high latency, while diffusion-based approaches are constrained by training-time configurations. Moreover, most flow-based methods operate in continuous space, which introduces optimization challenges because continuous token spaces are inherently more complex than discrete ones. To address these limitations, we propose DiFlow-TTS, a novel zero-shot TTS framework based on discrete flow matching. The model consists of a deterministic Phoneme-Content Mapper for linguistic modeling and a Factorized Discrete Flow Denoiser that simultaneously generates prosody and acoustic token streams. Experimental results demonstrate the effectiveness of our approach across multiple evaluation metrics.

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

cAPM: Continual AI-Assisted Pace-Mapping with Active Learning

arXiv:2606.19373v1 Announce Type: cross Abstract: Ventricular tachycardia is a life-threatening rhythm disorder and a major cause of sudden cardiac death. Pace-mapping is a clinical procedure for identifying the intervention target during catheter ablation of VT. It requires clinicians to pace different sites in the ventricles and rapidly interpret the resulting electrocardiograms to determine where to pace next or whether a target site has been identified. Active learning AI models have been proposed to guide clinicians to the next pacing site, showing promise in reducing the number of pacing sites and improving the efficiency of pace-mapping. Existing methods require retraining each target without the ability to transfer knowledge across multiple VTs within the same patient or across patients. We introduce cAPM for continuous AI-assisted pace-mapping to capture and transfer knowledge accumulated from past pace-mapping data to reduce the number of pace-mapping data needed for future target VTs. This is made possible by a task-agnostic surrogate neural network that learns the mapping from pacing sites to 12-lead ECG morphology, an active-learning strategy that refines this surrogate model by selecting the most informative pacing site for each target, and a continual learning strategy to do so sequentially while retaining knowledge from prior targets. Evaluated on an in-silico testbed consisting of sequentially-presented localization tasks across different physiological conditions and ventricular geometries, cAPM with and without replay of past data samples achieved an 81% probability of localizing within clinical tolerance (5 mm accuracy) using 4.5 pace-mapping sites, compared to the state-of-the-art active-learning method achieving 38% probability using 13.7 pacing sites. These results provide a strong basis for preparing cAPM towards in-vivo preclinical and clinical studies where it can be used to guide pace-mapping.

04.
arXiv (CS.CL) 2026-06-19

Your Mouse and Eyes Secretly Leak Your Preference: LLM Alignment using Implicit Feedback from Users

To align a Large Language Model (LLM), most existing methods collect explicit human feedback and train a reward model to predict the human preference based on the response text. These existing methods have two key limitations. First, the users rarely provide explicit feedback for LLM responses, which makes the high-quality preference annotation expensive to collect. Second, the methods do not leverage implicit human feedback, which has proven vital to the economic moats of Internet giants. To quantify the value of implicit feedback, we build a new dataset called IFLLM, which collects 1336 multi-turn questions from the 59 Mechanical Turk workers, their mouse trajectories, and eye gazing points to the LLMs' responses from their webcams. IFLLM shows that the users have very diverse types of gazing behavior and mouse trajectories. Our reward model based on the implicit user feedback boosts the accuracy of the text-based reward model from 55% to 64% and nearly triples the relative response quality improvements after applying the DPO to eight LLMs, demonstrating the value of implicit feedback in the wild. Our data collection website, dataset, and codes can be found at https://github.com/themehulpatwari/llm-implicit-feedback/.

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

From Correspondence to Actions: Human-Like Multi-Image Spatial Reasoning in Multi-modal Large Language Models

While multimodal large language models (MLLMs) have made substantial progress in single-image spatial reasoning, multi-image spatial reasoning, which requires integration of information from multiple viewpoints, remains challenging. Cognitive studies suggest that humans address such tasks through two mechanisms: cross-view correspondence, which identifies regions across different views that correspond to the same physical locations, and stepwise viewpoint transformation, which composes relative viewpoint changes sequentially. However, existing studies incorporate these mechanisms only partially and often implicitly, without explicit supervision for both. We propose Human-Aware Training for Cross-view correspondence and viewpoint cHange (HATCH), a training framework with two complementary objectives: (1) Patch-Level Spatial Alignment, which encourages patch representations to align across views for spatially corresponding regions, and (2) Action-then-Answer Reasoning, which requires the model to generate explicit viewpoint transition actions before predicting the final answer. Experiments on three benchmarks demonstrate that HATCH consistently outperforms baselines of comparable size by a clear margin and achieves competitive results against much larger models, while preserving single-image reasoning capabilities.

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

Pythagoras-Prover: Advancing Efficient Formal Proving via Augmented Lean Formalisation

arXiv:2606.12594v1 Announce Type: new Abstract: Modern Lean theorem provers achieve strong performance only with substantial training and inference compute, driven in part by scarce verified proof data and the long reasoning traces of formal proof search, making both supervised fine-tuning (SFT) and sampling expensive. We introduce Pythagoras-Prover, a compute-efficient open-source family of Lean theorem provers built for practical compute budgets. The family spans two generation paradigms: autoregressive models at 4B and 32B parameters, and a first proof-of-concept diffusion-based prover (4B) that iteratively refines Lean proofs at inference time. For training efficiency, we build a Lean-verified corpus stratified into easy, medium, and hard problems for curriculum SFT, so models acquire proof skills progressively from shorter, simpler proofs to longer, harder ones. During SFT, a dynamic proof-reasoning filtering scheme preserves informative proof traces while keeping each instance within an 8k-token context budget. We also introduce Augmented Lean Formalisation (ALF), which expands scarce verified corpora into variants of formal statements, populated via self-distillation for extra training signal without formally verifying every mutated instance. By perturbing known problems while preserving their formal character, ALF reduces reliance on any statement's surface form. Empirically, Pythagoras-Prover-4B surpasses DeepSeek-Prover-V2-671B at pass@32 on MiniF2F-Test (86.1% vs 82.4%) with ~167x fewer parameters, while Pythagoras-Prover-32B sets the open-source state of the art at 93.0% on MiniF2F-Test and solves 93 of 672 PutnamBench problems. We release MiniF2F-ALF, an ALF-mutated contamination-sensitive benchmark on which every evaluated model loses accuracy; here our 32B remains strongest and our 4B matches the prior state of the art, Goedel-Prover-V2-32B.

07.
arXiv (CS.CV) 2026-06-16

Sex-based Network-Specific Differences in Connectomes: A Krakencoder-Based Analysis

This study examines how deficiencies in one brain connectome modality propagate to the other, using the Krakencoder as a simulation framework. Structural and functional connectomes from 702 healthy participants in the Human Connectome Project were analyzed, with the impact of each of the Yeo-7 functional networks assessed separately. Seven scenarios were considered, each involving the removal of a single network while the remaining networks were preserved. The resulting perturbations in cross-modal predictions were quantified using three complementary metrics: KL divergence on eigenvalue spectra, Frobenius norm, and Wasserstein distance. In addition, the persistence of sex-specific information within the predicted connectomes was evaluated. Across all metrics and both prediction directions, the Default Mode Network produced the largest perturbations, whereas the Somatomotor network yielded the smallest. Sex differences in network-level perturbation signatures were subtle, with the best result being an accuracy of 66.09% from connectomes predicted under network-removal conditions. In contrast, connectomes predicted from intact inputs achieved substantially higher sex classification accuracy, reaching up to 84.76%. These findings confirm that full predicted connectomes retain considerably more sex-discriminative information than perturbation-derived signatures alone.

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

Simplifying the Modeling of Arbitrary Conditionals in Natural Language

Causal Transformers model sequences through an autoregressive factorization of the joint distribution, which enables efficient left-to-right decoding and conditional likelihood computation. However, they cannot tractably sample from or evaluate arbitrary conditionals – e.g., a block of text conditioned on past and future tokens. Recent work aims to solve this problem through novel architectures, but they often lead to sub-optimal modeling of such conditionals and degraded generations. We propose Arbitrary Conditionals GPT (AC-GPT) which introduces a simple modification to standard causal Transformers to enable evaluating and sampling from arbitrary conditionals – including past, future, and mixed contexts – within a single forward pass. Unlike prior approaches, our method preserves the standard left-to-right ordering and next-token prediction objective essential for both strong performance and efficient training on natural language. Crucially, this compatibility allows existing LLMs to be fine-tuned for arbitrary conditioning. Our empirical results indicate that our method outperforms baselines on modeling arbitrary conditionals, without degrading standard left-to-right performance.

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

Model Validation of Agentic AI Systems: A POMDP-Based Framework for Belief-State, Forecast, and Policy Validation

arXiv:2606.17383v1 Announce Type: cross Abstract: Agentic artificial intelligence systems introduce a new class of model risk. Unlike traditional predictive models, autonomous agents continuously acquire information, form beliefs regarding latent states of the environment, generate forecasts, select actions, and adapt their behavior over time. Existing validation methodologies focus primarily on predictive accuracy and therefore provide limited insight into the quality of the underlying decision process. This paper proposes a model validation framework for agentic AI based on Partially Observable Markov Decision Processes (POMDPs). The framework decomposes autonomous decision making into information, beliefs, forecasts, actions, and utility, allowing each component to be validated independently. Large language models (LLMs) are formalized as approximate Bayesian filtering operators, and a model-risk taxonomy is developed encompassing state-space, filtering, forecast, policy, utility-specification, and parameter risks. The model risk validation methodology is demonstrated through a portfolio-management case study in which an agent infers latent market regimes from market and macroeconomic information, generates belief-conditioned forecasts, and constructs portfolios using a Black–Litterman framework. Empirical validation combines performance analysis, belief calibration diagnostics, coverage tests, ablation studies, and parameter-sensitivity analysis. The results indicate that latent-state inference contributes independently to decision quality and that the principal conclusions remain robust across a broad range of parameter values. The principal contribution of the paper is a practical framework for extending established model risk management concepts to autonomous AI systems and providing a rigorous foundation for their validation, governance, and monitoring.

10.
arXiv (CS.AI) 2026-06-11

The Power of Test-Time Training for Approximate Sampling

arXiv:2606.11437v1 Announce Type: cross Abstract: Efficiently sampling from a complex probability distribution is a fundamental problem which has become increasingly pertinent in recent years with the rise of generative AI, as sophisticated sampling procedures from LLMs have been proposed to solve challenging reasoning problems. The efficacy of such sampling algorithms is limited, however, by the relationship between the LLM and the particular sampling task at hand, which has motivated the framework of test-time training (TTT). TTT works by updating a model's weights in response to partial generations and reward feedback received at inference time, thus adapting to the particular problem. In this work, we propose a formalization for TTT as the problem of producing a sample from a given probability measure $\mu^\star$ belonging to a known class ${F}$ of distributions, given an oracle $\hat \mu$ which yields approximate density estimates for $\mu^\star$. This is closely related to the problem of reducing sampling to approximate counting studied in seminal works of Jerrum, Valiant & Vazirani (1986) and Jerrum & Sinclair (1989): namely, when ${F}$ is the class of all distributions, it coincides exactly with the aforementioned counting-to-sampling reduction. In this paper, we first show a quadratic lower bound on the query complexity of sampling from $\mu^\star$ given query access to $\hat \mu$ (for sufficiently large classes ${F}$), thus showing that the random walk approach proposed by Jerrum & Sinclair (1989) and refined by Hayes & Sinclair (2010), is optimal. This answers an open question posed by Hayes & Sinclair. We then show that this lower bound can be circumvented if the size of ${F}$ is bounded appropriately. As we discuss, this latter result can be viewed as an abstraction of TTT, and thus represents a starting point for the development of a principled theoretical framework for TTT.

11.
arXiv (CS.LG) 2026-06-16

Data-driven Control with Real-time Uncertainty Compensation for Multi-Fuel Engines

arXiv:2606.16171v1 Announce Type: cross Abstract: Multi-fuel compression ignition (CI) engines offer superior power density and fuel flexibility. However, achieving consistent and optimal combustion phasing across a wide range of operating conditions remains a major challenge, particularly in the presence of modeling uncertainties. This paper presents a novel, data-driven real-time uncertainty compensation framework for combustion control in multi-fuel CI engines. The proposed approach introduces a pseudo-engine speed that enables dynamic adaptation of control inputs in response to uncertainty affecting the engine. To model the underlying combustion process, a Gaussian Process Regression (GPR) model is first trained on available input-output data, capturing the nonlinear and fuel-dependent behavior across varying operating conditions. Control inputs are then synthesized through model inversion of the learned GPR surrogate and augmented with an uncertainty compensator designed to mitigate deviations caused by dynamic variations in operating conditions and model inaccuracies. This integrated control strategy allows for real-time input corrections within a finite number of combustion cycles. Theoretical analysis establishes finite-time convergence guarantees for the proposed controller. Simulation results demonstrate that the proposed method steers the combustion phasing to the desired value in real-time, providing a scalable and adaptive control solution for multi-fuel CI engine operation.

12.
medRxiv (Medicine) 2026-06-22

Histologically validated diffusion MRI signatures of neuroinflammation and neurodegeneration in Alzheimer disease

Noninvasive neuroinflammation measurement remains a major barrier for Alzheimer disease (AD) therapeutics. We present generalized diffusion basis spectrum imaging (g-DBSI), a diffusion MRI framework that decomposes the tissue signal into biologically interpretable microstructural compartments. In postmortem Knight ADRC brains, g-DBSI-derived restricted isotropic fraction (RIF) and restricted anisotropic fraction (RAF) mapped cellularity and neurofilament density, while their ratio (RIF/RAF) tracked inflammatory cell density and peri-plaque amyloid-beta with higher specificity and regional consistency than RIF alone. In 112 living Knight ADRC participants stratified by PET amyloid, g-DBSI metrics showed amyloid-dependent trajectories: in low-amyloid individuals, RIF and RAF rose together with amyloid, consistent with early neuropil expansion and glial elaboration, whereas in high-amyloid individuals, RIF/RAF increased, and RAF declined, indicating established neuroinflammatory remodeling and neurofilament loss. CSF proteomics linked RIF/RAF to glia-enriched immune and vascular pathways, supporting g-DBSI as a clinically compatible MRI biomarker of neuroinflammation and neurodegeneration in AD.

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

DeXposure-Claw: An Agentic System for DeFi Risk Supervision

Decentralized finance exposes supervisors to fast-moving, networked credit risks. General-purpose LLM agents fit this setting poorly: they over-read weak evidence and recommend high-stakes interventions, while existing evaluations offer no regulator-aligned way to measure the resulting false alarms. We introduce DeXposure-Claw, a forecast-grounded agentic supervision system that routes LLM decisions through structured evidence: (1) DeXposure-FM, a graph time-series foundation model, forecasts future exposure networks; (2) deterministic monitors and stress scenarios then turn those forecasts into typed alerts, attribution signals, and scenario evidence; and (3) data-health and confidence gates constrain escalation before DeXposure-Claw emits auditable supervisory tickets with rationales. We further develop DeXposure-Bench, a six-axis evaluation harness, whose decision axis scores tickets against a regulator-aligned absolute-loss ground truth and an explicit false-intervention rate. Experiments on five years of weekly real data fully support our system. Code is at https://github.com/EVIEHub/DeXposure-Claw.

14.
arXiv (CS.AI) 2026-06-17

Brep2Shape: Boundary and Shape Representation Alignment via Self-Supervised Transformers

arXiv:2602.07429v2 Announce Type: replace-cross Abstract: Boundary representation (B-rep) is the industry standard for computer-aided design (CAD). While deep learning shows promise in processing B-rep models, existing methods suffer from a representation gap: continuous approaches offer analytical precision but are visually abstract, whereas discrete methods provide intuitive clarity at the expense of geometric precision. To bridge this gap, we introduce Brep2Shape, a novel self-supervised pre-training method designed to align abstract boundary representations with intuitive shape representations. Our method employs a geometry-aware task where the model learns to predict dense spatial points from parametric Bézier control points, enabling the network to better understand physical manifolds derived from abstract coefficients. To enhance this alignment, we propose a Dual Transformer backbone with parallel streams that independently encode surface and curve tokens to capture their distinct geometric properties. Moreover, the topology attention is integrated to model the interdependencies between surfaces and curves, thereby maintaining topological consistency. Experimental results demonstrate that Brep2Shape offers significant scalability, achieving state-of-the-art accuracy and faster convergence across various downstream tasks.Code is available at this repository: https://github.com/thuml/Brep2Shape.

15.
arXiv (CS.AI) 2026-06-17

Towards Understanding and Measuring COGNITIVE ATROPHY in LLM Behaviour

arXiv:2606.18129v1 Announce Type: cross Abstract: Recent incidents involving LLMs used for mental-health support reveal a critical evaluation gap: surface-level safety scores do not capture how models behave across realistic, emotionally sensitive interactions over time. Existing benchmarks measure knowledge, safety, or static response quality, but miss whether LLM interactions help users keep reflecting, coping, and making decisions themselves. We formalize this missing dimension as COGNITIVE ATROPHY, a process-level behavioural measure in AI-mediated mental-health support distinct from safety and helpfulness. To measure it, we introduce COGNITIVE ATROPHY BENCH, a clinically grounded benchmark built from 1,576 fully human-generated counseling conversations, 15,680 turns, and 42,230 responses from five LLMs. Three clinical and neuropsychology experts developed a 20-attribute schema spanning user context, response behaviour, and global risk flags; six trained clinical reviewers applied it with span-grounded evidence, producing 5,324 reviewer judgments. We further introduce the User-Input Risk Index (UIRI), the Cognitive Atrophy Risk Index (ARI), and trajectory summaries. Across five LLMs, models show a consistent moderate-to-high level of atrophy-aligned behaviour across single and multi-turn settings. While models generally respond to overt safety cues, they adapt less reliably when users seek solutions or decisions. The dominant recurring patterns are directive advice, problem-solving, recommendation responses, topic shifts, and forms of validation that may reinforce dependence rather than reflection. Our work makes COGNITIVE ATROPHY measurable and provides a foundation for auditing model behaviour in sensitive LLM conversations.

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

Data-Centric Benchmarking of Exploit Generation in LLMs: Understanding the Impact of Fine-Tuning

arXiv:2606.15123v1 Announce Type: cross Abstract: We study the task of CVE-conditioned exploit generation, where a model drafts proof-of-concept (PoC) exploits given software vulnerability context. We adopt a data-centric approach, constructing a high-quality dataset via multi-stage preprocessing and introducing a scalable evaluation framework with LLM-as-judge and fine-grained rubrics. Under this unified setup, we benchmark 17 large language models across 8 evaluation criteria, providing systematic insights into their zero-shot capabilities. We further show that a compact 8B open-weight model, when fine-tuned on curated data, achieves over 42.5% improvement in exploit quality and rivals some proprietary models when combined with simple test-time rejection strategies. Our results highlight the importance of data quality, structured supervision, and evaluation design for reliable exploit generation, suggesting that these factors can be as critical as model scale in adapting LLMs to cybersecurity tasks.

17.
arXiv (quant-ph) 2026-06-12

Stable, bidirectional electro-optic transduction in thin film lithium tantalate

arXiv:2606.12726v1 Announce Type: new Abstract: Efficient and stable microwave-optical transduction is a key enabling technology for distributed superconducting quantum computing and heterogeneous quantum networks. Electro-optic transducers based on thin-film lithium niobate (TFLN) have shown strong promise, but demonstrations to date have been limited by various factors such as low frequency bias drift, low efficiency, fabrication complexity, and scalability. Here we demonstrate the first integrated electro-optic microwave-optical transducers realized in thin-film lithium tantalate (TFLT), a material platform offering Pockels nonlinearity comparable to TFLN together with improved bias stability and high-power handling. We fabricate superconducting microwave resonators coupled to tunable photonic-molecule optical resonators using wafer-scale deep ultraviolet lithography, offering high-throughput production of hundreds of devices per wafer. Across six devices we observe coherent bidirectional conversion between C-band optical photons and 4.9-5.5 GHz microwave photons, with measured on-chip efficiencies and inferred single-photon coupling rates g_0/2{\pi} ~ 1 kHz consistent with theory. Continuous operation over multiple days is achieved using a static bias field with minimal feedback, demonstrating a major operational advantage. We further characterize optical loss statistics, microwave resonator performance, and optically induced added noise under pulsed pumping, finding less than one added photon for 100 microsecond pulses at the highest measured efficiencies. These results establish TFLT as a scalable and robust electro-optic platform for future quantum interconnects and modular quantum processors.

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

Privacy-Preserving Text Sanitization for Distributed Agents Collaboration via Disentangled Representations

When distributed agents exchange text across organizational boundaries, privacy leakage arises not only from explicit identifiers but also from distributional signatures such as formatting conventions, vocabulary choices, and syntactic patterns. We propose DiSan(Disentangled Sanitization), a privacy-preserving sanitization framework and a built-in component of Intern-Shannon for multi-agent collaboration. DiSan uses a two-stream encoder to factorize text into a source-invariant role subspace that preserves task semantics and a source-identifying style subspace that remains local. Federated proto-type alignment and adversarial regularization enable joint training without centralizing raw text. Experiments show that identifier-level masking is insufficient: masking 19.2% of tokens reduces TF-IDF stylometric attribution by only 18.6%. By contrast, DiSan reduces answer-level PII exposure by 20 times while maintaining 83% answer faithfulness on a distributed multi-agent RAG benchmark, and lowers Enron stylometric attribution by 73.2% under TF-IDF and 70.6% under a neural probe.

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

Double-Helix Vision (DH-V2): A Geometry-Based Visual Sampler for Bandwidth-Constrained Perception

作者:

We present Double-Helix Vision (DH), a geometry-based visual sampler that compresses 2D images into compact 1D signals using paired golden-ratio-inspired spiral trajectories. Rather than processing every pixel uniformly, DH employs two phase-shifted helices (Alpha and Beta, offset by 180 degrees) to sample the image with biologically-inspired foveation: high density at the center, sparse coverage at the periphery. At 4K resolution, DH achieves a 1,433x compression ratio (99.93% reduction) while preserving the geometric structure of the scene. The full perception pipeline – including spatial mapping, temporal collision detection, and intra-frame structural disparity estimation – runs in 0.52 ms at 1080p on CPU-only hardware, with no neural network dependencies. On CIFAR-10 at extreme sampling budgets (K=128 points per helix), DH achieves a +6.03% accuracy gain over uniform random sampling. A JSON-serializable Robotics API is provided, delivering sub-millisecond spatial perception reports in 2.7 KB packets. Code and benchmarks are available under the MIT License.

20.
Nature (Science) 2026-06-22

Why heritage sites are at risk in a warming world — and how to save them

As rising seas and intensifying disasters threaten historic sites worldwide, new ways to understand, preserve and adapt these places are needed urgently. As rising seas and intensifying disasters threaten historic sites worldwide, new ways to understand, preserve and adapt these places are needed urgently.

21.
medRxiv (Medicine) 2026-06-22

T Cell Receptor repertoire analysis reveals antigenic convergence and immunotherapeutic opportunities in Prostate Cancer

Background: The T-cell receptor {beta} (TCR{beta}) repertoire reflects antigen-driven adaptive immune responses and provides insight into tumor-immune interaction. In prostate cancer (PCa), the immunosuppressive tumor microenvironment limits effective T-cell activation, and the antigenic drivers shaping intratumoral TCR repertoires remains poorly defined. This study aimed to characterize matched tumor and peripheral TCR{beta} repertoires from treatment-naive PCa patients and to identify shared clonotypes and antigenic specificities associated with disease severity. Methods: Next-generation sequencing was used to profile TCR{beta} repertoires from matched tumor biopsies and peripheral blood mononuclear cells obtained from treatment-naive PCa patients. Repertoires clonality, diversity, and was assessed using established metrics. Antigenic convergence was evaluated using GLIPH2 to identify shared CDR3{beta} motifs and predicted tumor-associated antigen (TAA) recognition, followed by functional validation using IFN-{gamma} ELISpot and T-cell expansion assays. Results: Tumor-derived TCR{beta} repertoires displayed reduced richness and increased clonality compared with peripheral blood mononuclear cells, consistent with local antigen-driven expansion. High-grade tumors demonstrated greater interpatient clonotype sharing and motif-level convergence, indicative of recognition of common TAAs. GLIPH2 analysis associated expanded clonotypes with epitopes derived from prostate-specific G-protein coupled receptor (PSGR), prostate-specific membrane antigen (PSMA), and prostate-specific antigen (PSA). Functional validation confirmed that peptide pools containing PSGR- and PSMA-derived epitopes induced IFN-{gamma} production and antigen-specific T-cell proliferation in vitro. Conclusions: These findings reveal an oligoclonal, antigen-driven intratumoral TCR{beta} landscape and identify PSGR and PSMA as immunogenic, potentially actionable targets. Integration of TCR profiling with antigen discovery pipelines may support the development of TCR-based biomarkers and precision immunotherapeutic strategies in prostate cancer.

22.
medRxiv (Medicine) 2026-06-15

Entity-Aware Generation of Synthetic Clinical Progress Notes for Prostate Cancer using Large Language Model

Objectives: This study investigates large language models (LLMs) for clinical entity projection across substantial textual transformation. Specifically, we evaluate whether entities annotated in Spanish prostate cancer case reports can be preserved and explicitly projected when the source narratives are transformed into hospital-style clinical progress notes. Entity projection is treated as a generation-driven task, allowing paraphrase, condensation and narrative reorganisation, providing that clinically relevant entities remain recoverable as structured annotations. Methods: A corpus of 109 Spanish prostate cancer case reports was annotated using a silver-standard pipeline combining Spanish biomedical named-entity recognition with rule-based prostate-specific antigen (PSA) and Gleason extractors. The resulting silver-standard annotations were validated on a subset of generated notes against a gold-standard consensus produced by medical experts in prostate cancer. Four LLMs were evaluated for note generation and entity projection: GPT-5.4 Nano, Qwen 3.5:35B-A3B, GLM5 and Claude Sonnet 4.6. Entity-to-Entity (E2E) generation used XML-annotated cases as RAG-supported input, whereas Text-to-Entity (T2E) generation required models to generate and annotate notes directly from plain text cases. Zero-shot and few-shot prompting were tested. Projection quality was measured using precision, recall and F1-score, and complemented by LLM-as-a-judge evaluation using Kimi K2.6. Results: E2E consistently outperformed T2E, indicating that explicit entity-enriched in- put substantially facilitates entity preservation and localisation. GLM5 achieved the best E2E zero-shot result (F1 = 0.915), followed by Claude Sonnet 4.6 (F1 = 0.896). In T2E, few-shot prompting improved performance, with Claude Sonnet 4.6 reaching the highest score (F1 =0.718). Age, Gleason, Disease, Procedure, Duration and negation-related entities were robustly projected, whereas PSA and Dose showed less stable behaviour. Conclusion: LLMs can generate clinically plausible synthetic prostate cancer evolution notes while preserving a substantial proportion of source entities, particularly when explicit semantic annotations are provided as input. However, the lower and more variable performance observed in T2E highlights the difficulty of jointly generating clinical narratives and projecting entities without source-side information, especially for numerical and measure-related entities.

23.
arXiv (quant-ph) 2026-06-16

Retrocausal capacity of a quantum channel: Communicating through noisy closed timelike curves

arXiv:2509.08965v3 Announce Type: replace Abstract: We study the capacity of a quantum channel for retrocausal communication, where messages are transmitted backward in time, from a sender in the future to a receiver in the past, through a noisy postselected closed timelike curve mathematically represented by the channel. We completely characterize the one-shot retrocausal quantum and classical capacities, and we show that the corresponding asymptotic capacities are equal to the average and sum, respectively, of the channel's max-information and its regularized Doeblin information. This endows these information measures with a novel operational interpretation. Furthermore, our characterization can be generalized beyond quantum channels to all completely positive maps. This imposes information-theoretic limits on transmitting messages via postselected-teleportation-like mechanisms with arbitrary initial- and final-state boundary conditions, including those considered in various black-hole final-state models.

24.
Nature Medicine 2026-06-15

Activity-dependent adaptive deep brain stimulation improves gait in Parkinson’s disease

Parkinson’s disease leads to a spectrum of locomotor deficits that vary in severity with the nature of daily activities and the fluctuating physiology of patients. Many of these deficits remain inadequately addressed by existing deep brain stimulation therapies that rely on activity-agnostic parameters optimized for cardinal motor symptoms. By contrast, therapies embedding activity-specific parameters have the potential to better address the entire range of symptoms. Here we expose physiological principles that enable real-time decoding of ongoing locomotor activities across motor fluctuations from the neural dynamics of the subthalamic nucleus. This decoding steered activity-dependent adaptations of deep brain stimulation therapies that improved locomotor deficits while preserving efficacy for cardinal motor symptoms across activities of daily living. Our activity-dependent framework provides a blueprint for next-generation neuromodulation therapies that continuously select parameters optimized to the behavioral context and fluctuating physiology of each patient. ClinicalTrials.gov registration NCT06791902 . Neural decoding algorithms that leverage physiological principles of locomotor encoding support activity-dependent deep brain stimulation therapies that improve locomotor deficits in people with Parkinson’s disease.

25.
arXiv (CS.LG) 2026-06-16

libhmm: A Modern C++20 Library for Hidden Markov Models with Correct MLE Emission M-Steps

作者:

arXiv:2605.29208v2 Announce Type: replace-cross Abstract: We describe libhmm, a C++20 library for Hidden Markov Model parameter estimation, sequence decoding, and model selection. libhmm addresses two gaps in existing software: the absence of a well-maintained, zero-dependency C++ HMM library suitable for embedding in production systems, and the widespread use of method-of-moments (MOM) approximations in the emission distribution M-step of the Baum-Welch algorithm. The library implements correct maximum likelihood estimators for sixteen scalar emission distributions, including an ECME algorithm for the location-scale Student-t distribution, Newton-Raphson maximization for Gamma, Beta, Weibull, and Negative Binomial distributions, and the von Mises distribution for circular data. All forward-backward and Viterbi calculations operate in full log-space. SIMD acceleration is provided for AVX-512, AVX2, SSE2, and ARM NEON via compile-time dispatch with scalar fallback. Version 4 adds multivariate observation support via the BasicHmm template, with three multivariate emission families (diagonal Gaussian, full-covariance Gaussian, and independent components) each with correct weighted MLE M-steps. Python bindings are available via the companion package pylibhmm. We compare libhmm against established C and C++ HMM libraries and against published R reference packages on seven real-data benchmarks, and discuss the architectural tradeoffs made in the design.