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01.
arXiv (CS.AI) 2026-06-12

Divination by Prompt: LLM-Mediated Xuanxue on Chinese Social Media

arXiv:2606.12418v1 Announce Type: cross Abstract: The rapid proliferation of large language models (LLMs) has produced a striking cultural practice: using conversational AI for divination. This paper offers one of the first systematic studies of LLM-mediated divination in the context of Xuanxue, an internet-native umbrella term for mystical and spiritual practices on Chinese social media. Using a mixed-methods design, we analyze 23000+ posts and comments from Xiaohongshu and conduct 32 semi-structured interviews with users and professional diviners. Users primarily consult LLMs about pragmatic concerns - romantic relationships, careers, exams, and in-game gacha draws - via two intersecting pathways: trend-driven curiosity enabled by viral visibility and zero-cost access, and event-driven anxiety under conditions of uncertainty. A defining feature is collaborative prompt refinement, which turns users into active prompt engineers. Among commenters expressing a clear stance, perceived efficacy skews positive, with "accuracy" often justified through biographical fit and retrospective confirmation, consistent with Barnum and confirmation bias. Users also develop verification practices such as repeated trials and cross-model comparison. Professional diviners, by contrast, portray LLMs as lacking the "spiritual power" required for genuine divination, reflecting both ontological commitments and economic boundary-work. We also show how participants navigate tensions between scientific and metaphysical frames when interpreting AI-generated readings. Situating these findings in anthropological and cognitive-evolutionary theories of divination, we argue that LLM divination preserves core functions of traditional practice while introducing scalability, repeatability, and prompt-driven co-production that reshape how divinatory authority is constructed and evaluated.

02.
arXiv (CS.CV) 2026-06-19

Efficiently Linking Real Scenes with Synthetic Data Generation for AI-based Cognitive Robotics and Computer Vision Applications

AI vision models are a driving factor for the potential use case scenarios of cognitive robotics within in the industry and household applications. A large array of methods from semantic environment analysis towards 6D and grasping pose estimation have been proposed based on the latest AI achievements. However, such advancements require further strong and efficient methods w.r.t. training data and AI-architectures, which are capable in synergy to tackle current challenges, precision limits, and scalability beyond domain gaps. In this paper, we discuss these current limits and trends in the related state-of-the-art which are challenging those. Further we discuss our current work in progress on bridging the domain gap between simulations and real world applications by linking those in the training data generation.

03.
arXiv (CS.CV) 2026-06-17

FATE: Pillar Encoding and Frequency-Aware Training for Event-Based Object Detection

Event cameras are bio-inspired sensors that asynchronously capture logarithmic intensity changes, offering inherent advantages in high-speed and high-dynamic-range scenarios. However, the sparse and asynchronous nature of event streams poses a fundamental challenge for modern deep learning architectures. To enable compatibility with standard models, most existing approaches partition the accumulation window into fixed temporal sub-bins. While effective for spatial processing, this internal discretization discards fine-grained temporal structure and constrains inference to the low temporal frequencies imposed by training supervision. To address this limitation, we propose FATE, a unified framework built upon a novel Pillar Encoding (PE). While operating over discrete macro-accumulation windows dictated by the target frequency, PE avoids internal temporal sub-binning. It organizes events into spatial pillars and approximates their intra-window evolution via projection onto a continuous-time orthogonal polynomial basis. This formulation yields an L2-optimal representation that retains rich temporal dynamics in a dense pseudo-image, mitigating information loss under sparse event conditions. To fully leverage this representation, we introduce Frequency-Aware Training (FAT), a soft mean-teacher curriculum that generates temporally dense pseudo-labels, effectively bridging the mismatch between low-frequency supervision and high-frequency inference. Extensive experiments demonstrate that FATE generalizes across architectural paradigms and consistently outperforms strong baselines. It enables robust object detection at high temporal resolutions up to 200 Hz, while incurring minimal overhead in parameter count and inference latency

05.
arXiv (quant-ph) 2026-06-11

Polarization-Resolved Photon Statistics of Cavity Quantum Materials

arXiv:2606.11550v1 Announce Type: cross Abstract: By forming hybrid light-matter states, optical cavities offer a route for engineering material properties, however, unambiguously probing the effects of light-matter coupling remains difficult. Here, we show that the polarization-resolved statistics of photons transmitted through a cavity, measurable via $g^{(2)}$, provide one such diagnostic. By relating $g^{(2)}$ to matter correlation functions such as the Raman structure factor, we link photon bunching and antibunching to material properties. By applying this method to the stripy-to-antiferromagnetic transition in the Kitaev-Heisenberg spin model, we find that polarization-dependent patterns of bunching and antibunching encode the magnetic point-group symmetries of each phase and characterize the behavior at the phase boundary. Finally, we predict measuring $g^{(2)}$ for output photon pairs polarized orthogonal to the input field will isolate higher-order light-matter scattering processes that probe higher-order material correlations.

06.
Nature Medicine 2026-06-17

Why large-scale randomized trials of live-attenuated shingles vaccination for dementia prevention are urgently needed

In my view, we have never had as robust a body of evidence from observational data on an intervention for dementia as we do for live-attenuated shingles vaccination. Both a recent US National Institutes of Health expert workshop and an international expert consensus on Alzheimer’s disease drug repurposing identified large-scale randomized trials of shingles vaccination for dementia prevention as the crucial next step for the field.

07.
arXiv (CS.AI) 2026-06-17

Detecting and Mitigating DDoS Attacks with AI: A Survey

arXiv:2503.17867v3 Announce Type: replace-cross Abstract: Distributed Denial of Service attacks represent an active cybersecurity research problem. Recent research shifted from static rule-based defenses towards AI-based detection and mitigation. This comprehensive survey covers several key topics. Preeminently, state-of-the-art AI detection methods are discussed. An in-depth taxonomy based on manual expert hierarchies and an AI-generated dendrogram are provided, thus settling DDoS categorization ambiguities. An important discussion on available datasets follows, covering data format options and their role in training AI detection methods together with adversarial training and examples augmentation. Beyond detection, AI based mitigation techniques are surveyed as well. Finally, multiple open research directions are proposed.

08.
arXiv (CS.LG) 2026-06-17

Clarify Before You Draw: Proactive Agents for Robust Text-to-CAD Generation

arXiv:2602.03045v2 Announce Type: replace Abstract: Large language models have recently enabled text-to-CAD systems that synthesize parametric CAD programs (e.g., CadQuery) from natural-language prompts. In practice, however, geometric descriptions can be under-specified or internally inconsistent: critical dimensions may be missing and constraints may conflict. However, existing fine-tuned models tend to reactively follow the user instructions and hallucinate dimensions when the text is ambiguous. To address this, we propose a proactive agentic framework for text-to-CadQuery generation, named as ProCAD, that resolves specification issues before code synthesis. Our framework pairs a proactive clarifying agent, which audits the prompt and asks targeted clarification questions only when necessary to produce a self-consistent specification, with a CAD coding agent that translates the specification into an executable CadQuery program. We fine-tune the coding agent based on a curated high-quality text-to-CadQuery dataset and train the clarifying agent via agentic SFT on clarification trajectories. Experiments show that proactive clarification significantly improves robustness to ambiguous prompts while keeping interaction overhead low. ProCAD outperforms frontier closed-source models, including Claude Sonnet 4.5, reducing the mean Chamfer distance by 79.9% and lowering the invalidity ratio from 4.8% to 0.9%. Our code and datasets are made publicly available on https://github.com/BoYuanVisionary/Pro-CAD.

09.
bioRxiv (Bioinfo) 2026-06-16

Accelerating String Comparison in RLZ Compressed Sequences via LCE Jumps

Relative Lempel-Ziv (RLZ) is an effective compression method for large, repetitive collections; however, the fundamental primitives required to elevate it from a passive archival format to a tractable representation for compressed construction have yet to be fully established. In this paper, we introduce an algorithmic framework for structurally comparing and lexicographically sorting sequences of RLZ factors. We characterize when direct factor comparisons are necessary and when they can be bypassed using RLZ specific shortcuts. We further introduce a method for extending truncated factors into right-maximal matches, enabling the recovery of matching statistics from the RLZ parse. Experimentally, RLZ sorting achieved speedups of up to 3.93x over character-based sorting. Together, these results advance the use of the RLZ format as a foundation for compressed construction.

10.
arXiv (CS.LG) 2026-06-15

Time Series Causal Discovery via Context-Conditioned and Causality-Augmented Pretraining

arXiv:2605.26759v2 Announce Type: replace Abstract: Causal discovery from time series is critical for many real-world applications, such as tracing the root causes of anomalies. Existing approaches typically rely on dataset-specific optimization, making it difficult to transfer their causal discovery capabilities to new time series governed by diverse causal mechanisms. In this paper, we propose PTCD, a novel Pretraining framework for Time-series Causal Discovery, which improves cross-task generalization through context-conditioned modeling and transferable causal augmentation. To model complex temporal causal dependencies, PTCD employs a dual-scale iterative attention mechanism to capture window-level causal relationships, and a Gaussian mixture with a context-level routing mechanism to handle heterogeneous exogenous distributions. To further address distribution shifts across causal graphs, PTCD adopts a pretraining paradigm on synthetic datasets that integrates intervention-based learning and a causal mixup strategy, promoting stable causal discovery and stronger generalization. Extensive experiments on multiple real-world out-of-distribution (OOD) datasets demonstrate that PTCD excels in both causal discovery and root cause identification.

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

FOCUS: DLLMs Know How to Tame Their Compute Bound

Diffusion Large Language Models (DLLMs) offer a compelling alternative to Auto-Regressive models, but their deployment is constrained by high decoding cost. In this work, we identify a key inefficiency in DLLM decoding: while computation is parallelized over token blocks, only a small subset of tokens is decodable at each diffusion step, causing most compute to be wasted on non-decodable tokens. We further observe a strong correlation between attention-derived token importance and token-wise decoding probability. Based on this insight, we propose FOCUS, an inference system designed for DLLMs. By dynamically focusing computation on decodable tokens and evicting non-decodable ones on-the-fly, FOCUS increases the effective batch size, alleviating compute limitations and enabling scalable throughput. Empirical evaluations demonstrate that FOCUS achieves up to 3.52$\times$ throughput improvement over the production-grade engine LMDeploy in large-batch settings, while preserving or improving generation quality across multiple benchmarks.

12.
arXiv (CS.AI) 2026-06-16

Deep Q-Learning on Hölder Spaces

作者:

arXiv:2606.16846v1 Announce Type: cross Abstract: We study the operator-theoretic core of Q-learning in continuous-time stochastic control with continuous states and actions. In value-based reinforcement learning, each Q-learning or DQN update is built from a Bellman optimality target; our analysis isolates this target in a diffusion setting and studies its regularity and approximation complexity. Under uniform ellipticity and Hölder-regular coefficients, we show that a Bellman update maps bounded inputs into an anisotropic regularity class, smoothing the state variable while leaving only Lipschitz dependence on the action variable. This yields a compact family of Bellman iterates and motivates a tensor-product DeepONet architecture adapted to the mixed regularity of the problem. We then derive explicit approximation and resource bounds, together with a stiffness–complexity trade-off as the time step $\delta \to 0$. The resulting theory makes a direct contribution to Q-learning theory at the level of Bellman target regularity and approximation in continuous stochastic control. At the same time, we do not claim a full convergence theorem for practical sampled Q-learning with exploration, replay, and stochastic gradient updates.

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

The Morse Transform for Discrete Shape Analysis

arXiv:2503.04507v2 Announce Type: replace-cross Abstract: The geometry of an object plays a vital role in modulating its interactions with the physical world. It nevertheless remains difficult to describe geometric information numerically for the purposes of statistical inference or classification tasks. Here, we introduce a new topological transform which leverages directional piecewise-linear Morse theory to quantify the geometry of an embedded object by cataloguing critical points across multiple height-functions. The output of this Morse transform records both the heights and the local topological type (peak, trough or saddle) of the critical points that characterise the underlying shape, retaining finer information than the Euler characteristic transform whilst naturally prioritising a shape's outermost regions. Crucially, this output can be further compressed into a rich but compact feature vector. We benchmark the Morse feature vector as a descriptor for ligand-based virtual screening (LBVS), which intrinsically depends on the shape of molecules. Under a common gradient-boosted tree classification pipeline, Morse descriptors achieve the highest mean AUROC when compared to other topological transform descriptors and to standard shape-based LBVS descriptors.

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

Contactless Respiratory Monitoring on Heterogeneous Mobile Robots: A Multimodal Edge-Computing Framework

Respiratory-rate (RR) monitoring is a critical component of remote triage and victim assessment in emergency response, disaster recovery, and infectious-disease scenarios, where minimizing physical contact can reduce responder risk and improve operational safety. However, field deployment of contactless RR monitoring remains challenging due to variable illumination, posture changes, platform heterogeneity, and the impracticality of wearable sensors in hazardous environments. In this paper, we present a modality-adaptive contactless RR monitoring framework for heterogeneous mobile robots with onboard edge computing. The proposed system combines brightness-adaptive sensor selection across RGB, thermal, near-infrared (NIR), and low-light cameras, keypoint-guided chest ROI extraction for posture-robust monitoring, and a signal-quality-index (SQI)-based filtering mechanism for reliable respiratory estimation. We implement and evaluate the framework on three robotic platforms spanning quadruped and wheeled locomotion and multiple edge-computing architectures. Experiments conducted across diverse lighting conditions, subject poses, and robot-to-subject distances demonstrate that the framework generalizes across platforms without per-platform algorithmic retuning, while revealing modality-specific operational boundaries. RGB provides the broadest coverage up to 8m, NIR remains effective up to 6m, thermal is reliable only at short range, and low-light sensing supports monitoring in complete darkness up to 8m. Overall, the results demonstrate the feasibility of multimodal contactless RR monitoring on mobile robots and support its use as a foundation for autonomous triage and victim assessment in hazardous search-and-rescue settings.

15.
bioRxiv (Bioinfo) 2026-06-11

Combinatorial docking and molecular generation to navigate over 100-billion molecules for prospective ligand discovery

Commercially available make-on-demand libraries now exceed 100 billion compounds, requiring over 50 years to screen on 2,000 CPU cores using conventional docking. We present two complementary approaches to address this challenge. CombiDOCK, a combinatorial docking framework, enables exhaustive screening at the 100-billion scale within 40 days. MINT-Dock, a generative framework, accelerates navigation of this space by integrating CombiDOCK with Monte Carlo Tree Search. Benchmarked on 46 diverse targets, CombiDOCK matched full-molecule docking accuracy, and MINT-Dock achieved a 4,800-fold enrichment over random selection. Compared with prior billion-scale brute-force campaigns against {sigma}2, VMAT2, and VAChT, prospective CombiDOCK screens of the 100-billion-molecule library yielded higher hit rates and more potent ligands, while MINT-Dock achieved comparable outcomes across single- and multi-target objectives with >20-fold computational cost reductions. Docking-predicted poses of the best VAChT-binding compounds were confirmed by cryo-EM structures. These methods provide exhaustive and generative paths for navigating the trillion-molecule frontier of drug discovery.

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

Verifiable Environments Are LEGO Bricks: Recursive Composition for Reasoning Generalization

Reinforcement Learning (RL) with verifiable environments has emerged as a powerful approach for enhancing the reasoning capabilities of Large Language Models (LLMs). While prior research demonstrates that scaling environment quantity improves RL performance, existing manual or individual construction methods suffer from linear scaling limits, thereby hindering scalable reasoning generalization. This paper introduces RACES (Recursive Automated Composition for Environment Scaling), a framework that conceptualizes verifiable environments as composable building blocks that can be recursively assembled. The key insight is that when the codomain (output type) of one environment matches the domain (input type) of another, they can be automatically fused into a new verifiable environment, enabling recursive composition. RACES is implemented with 300 individual environments and defines a set of composition operators (\textsc{SEQUENTIAL}, \textsc{PARALLEL}, \textsc{SORT}, and \textsc{SELECT}) that induce diverse reasoning patterns. Extensive experiments show that RL training on these composite environments consistently enhances reasoning generalization. Specifically, RACES improves DeepSeek-R1-Distill-Qwen-14B by an average of 3.1 points (from 48.2 to 51.3) and boosts Qwen3-14B performance from 58.8 to 61.1 on six benchmarks, which are unseen during the construction of training environments. Moreover, RACES achieves performance comparable to training on 300 individual environments using only 50 base environments, demonstrating significant efficiency in environment utilization.

17.
arXiv (CS.AI) 2026-06-18

A Variational Framework for LLM Generator-Regulator Games

作者:

arXiv:2606.18424v1 Announce Type: cross Abstract: This paper develops a variational framework for regulated language generation. Starting from autoregressive token sampling, we derive the induced distribution over complete messages and relate it to an entropy-regularized Gibbs law. Regulation is modeled as an optimal discriminator whose convex-dual value is an f-divergence, and the generator-regulator interaction is formulated as a saddle-point problem. The framework applies to moderation, censorship, AI deception detection, compliance auditing, phishing defense, and manipulation control, where regulation concerns a distribution over possible messages rather than a single output. The equilibrium clarifies the tradeoff among utility, entropy, regulatory alignment, and finite-length detectability. Two finite-vocabulary case studies, censorship filtering and phishing defense, illustrate how the theory can be evaluated through utility, entropy, divergence, receiver-side scores, and detection probability.

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

ST-DiffEye: Diffusion-based Continuous Gaze Generation via Joint Scanpath-Trajectory Modeling

We study the problem of human gaze modeling, which aims to generate the gaze patterns a viewer produces while observing a visual stimulus. Gaze is primarily captured through two modalities: continuous eye-tracking trajectories, which describe fine-grained motion dynamics, and discrete scanpaths, which describe high-level fixation structure. Because gaze varies substantially across viewers and trials, we treat this variability as a defining property rather than noise and model gaze as a stochastic generative process. Existing generative gaze models supervise on only one of these two representations in isolation. We hypothesize that trajectories and scanpaths describe gaze at complementary scales and are jointly informative during training, and test this hypothesis through ST-DiffEye, a joint trajectory-scanpath diffusion framework that couples both modalities by concatenating them as an additional raw input channel, requiring no architectural overhead beyond an input and output channel expansion. We further introduce a principled evaluation framework based on the Continuous Ranked Probability Score (CRPS), which generalizes any existing sequence similarity metric into a proper scoring rule that jointly assesses the accuracy and diversity of generated gaze. Experiments on task-driven visual search, covering both target-present and target-absent scenarios, and on free-viewing benchmarks demonstrate state-of-the-art performance. These results, along with detailed ablations, confirm the benefit of joint modeling and the value of distribution-aware evaluation in capturing the intrinsic variability of human gaze. Project webpage: https://st-diffeye.github.io/

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

VeriGeo: Controllable Geometry Question Generation with Numerical and Analytical Verification

arXiv:2606.14176v1 Announce Type: new Abstract: Geometry problem generation is useful for AI-assisted education and multimodal mathematical reasoning, but reliable synthesis remains difficult because the problem statement, diagram, constraints, and solution should be mutually consistent. Existing methods often trade off controllability and reliability: seed-based rewriting is flexible but weakly verifiable, whereas diagram-first construction improves validity but is less suited to arbitrary user-specified constraints. We introduce VeriGeo, a controllable geometry generation framework grounded in executable reasoning traces. Given user constraints such as target concepts and difficulty, an Author agent generates a problem and diagram, and a Solver agent produces a proof-aligned solution. Both agents use a shared action sequence that connects natural language, diagrams, geometric constraints, and proof steps into a verifiable representation. A three-stage pipeline checks numerical consistency, analytical realizability, and global consistency, using verification-guided reflection to repair recoverable failures and reject unrecoverable ones. Across five LLM backbones, raw generations frequently fail these checks, while VeriGeo repairs a substantial fraction of the invalid attempts. Supervised fine-tuning on 8.7k examples generated by VeriGeo achieves the best reported GeoQA performance among end-to-end multimodal LLM-based solvers, and obtains strong results on PGPS9K and MathVista-GPS, demonstrating the effectiveness of verified synthetic data for improving multimodal geometry reasoning.

20.
arXiv (quant-ph) 2026-06-19

Progress on the Kretschmann-Schlingemann-Werner Conjecture

arXiv:2308.15389v4 Announce Type: replace Abstract: Given any pair of quantum channels $\Phi_1,\Phi_2$ such that at least one of them has Kraus rank one, as well as any respective Stinespring isometries $V_1,V_2$, we prove that there exists a unitary $U$ on the environment such that $\|V_1-({\bf1}\otimes U)V_2\|_\infty\leq\sqrt{2\|\Phi_1-\Phi_2\|_\diamond}$. Moreover, we provide a simple example which shows that the factor $\sqrt2$ on the right-hand side is optimal, and we conjecture that this inequality holds for every pair of channels.

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

When Context Returns: Toward Robust Internalization in On-Policy Distillation

arXiv:2606.11627v1 Announce Type: cross Abstract: Recent work has shown that on-policy distillation can internalize privileged context, such as system prompts or task hints, into a student model so that the context is no longer needed at inference time. Although this approach successfully improves the student's no-context performance, we identify an interesting and previously unstudied phenomenon: in many settings, reintroducing the original privileged context to the distilled student actually degrades its performance, even on instances it already solves correctly without context. We term this context-induced degradation and argue that robust internalization demands not only matching the teacher's context-conditioned behavior, but also remaining stable when the context is reintroduced, a property we call context removability. Motivated by this observation, we propose a lightweight consistency regularizer that first anchors the student's no-context output via stop-gradient, then penalizes the context-conditioned output for deviating from it via forward KL divergence. This simple addition requires only one extra forward pass per training step, yet it effectively mitigates context-induced degradation and, in many cases, even improves no-context performance. Across 12 configurations spanning diverse domains and model families, our method improves context-conditioned accuracy in the majority of settings, reduces context-induced harm in 11 out of 12 settings, and effectively eliminates response-length inflation. A mechanistic case study further confirms that context removability is achieved at the representation level, with hidden states remaining nearly identical regardless of whether the context is present.

22.
arXiv (CS.CV) 2026-06-11

On the Study of Biometric Spoofing Detection using Deep Learning

Biometric systems are increasingly deployed in security applications; however, they remain vulnerable to spoofing attacks, in which attackers exploit counterfeit biometric data to gain unauthorized access. This research evaluates the effectiveness of state-of-the-art machine learning models, MobileNetV2, DenseNet-121, Inception-v3, and Spoof Trace Disentanglement (STD) in detecting spoofing attacks within facial recognition systems. Using the CelebA-Spoof dataset, the study evaluates model effectiveness using metrics such as accuracy, precision, recall, and F1 Score. Cross-dataset validation is carried out on the MSU-MFSD dataset to assess generalizability. The results show MobileNetV2 as the most efficient model, achieving 92% accuracy while balancing computational effectiveness, making it appropriate for real-life applications. Inception-v3 shows moderate robustness, while DenseNet-121 and STD struggle with generalization. The findings highlight the need for advances in domain adaptation and hybrid architectures to enhance biometric security systems.

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

Charging Quantum Batteries with Chiral Squeezing

arXiv:2606.16764v1 Announce Type: new Abstract: We propose a quantum-battery charger based on a driven bosonic Kitaev chain (BKC), where chiral squeezing converts passive input fluctuations into ordered, non-passive battery states. While a coherent input pulse exhibits phase-sensitive chiral transport, the charging dynamics is dominated by bidirectionally propagating fluctuations that are amplified and squeezed into orthogonal quadratures at opposite chain ends. In contrast to conventional phase-preserving amplifiers, our scheme stores largely extractable energy and achieves a work-like signal-to-noise ratio (SNR) near unity, even in the presence of thermal noise and moderate symmetry-preserving disorder.

24.
arXiv (CS.CL) 2026-06-12

Leveraging Audio-LLMs to Filter Speech-to-Speech Training Data

Large-scale mined corpora provide abundant training data for end-to-end speech-to-speech translation (S2ST) but may contain noise, misalignment, and semantic errors. Filtering noisy data is crucial to maintain robust speech translation performance. We study how to train an audio-language model to make keep/drop decisions on paired speech directly from audio. To obtain reliable supervision without manual labels, we adopt a scalable two-stage Rank-to-Distill strategy. A lightweight ranker generates keep/drop pseudo-labels from noisy speech pairs, then trains an audio large language model to predict keep/drop directly from raw paired speech. The resulting model jointly captures acoustic fidelity and cross-lingual semantic consistency for the selection of speech-conditioned data. Experiments on CVSS-C and SpeechMatrix show consistent improvements over unfiltered training, yielding up to +1.4 ASR-BLEU for end-to-end S2ST.

25.
medRxiv (Medicine) 2026-06-15

Long-read sequencing enables high-accuracy mitochondrial heteroplasmy detection in Parkinson's disease

Background: Low-frequency heteroplasmic mitochondrial DNA (mtDNA) variants are associated with aging and neurological diseases, including Parkinson's disease (PD). Targeted deep mtDNA sequencing using PacBio HiFi long reads has the potential to resolve heteroplasmy across the full mitochondrial genome with high accuracy. Methods: To validate Vega PacBio sequencing for detecting mtDNA heteroplasmy, we analyzed four predefined mixtures of two mtDNA haplotypes. We generated a single long-range PCR amplicon covering the entire mitochondrial genome. These amplicons were mixed at predefined ratios (minor mixture haplotype component: 5%, 2%, 1%, and 0.1%). Variant calling was performed using Mutserve2, and accuracy was assessed by calculating the F1 score from comparisons between expected and detected variants. Full-length mtDNA PacBio sequencing was applied to investigate heteroplasmy across fibroblast passages derived from five LRRK2 p.Gly2019Ser variant carriers (n=3 affected with PD and n=2 unaffected carriers). Changes in mtDNA heteroplasmy level and variant load were assessed longitudinally using a linear mixed model. Results: The single-amplicon approach enabled full-length haplotype resolution without amplification bias associated with overlapping PCR strategies. The F1 score of the predefined mixtures was 1.0 for heteroplasmy levels between 5% and 1% and remained high (0.91) at 0.1%. We detected n=10/62 variants discordant with the Illumina reference at the 0.1% mixture, but sensitivity remained very high at 1.00 in that mixture. Detected minor variants closely matched expected heteroplasmy levels, with average variant levels of 0.057 (5%), 0.022 (2%), 0.011 (1%), and 0.001 (0.1%). Across twelve fibroblast passages, we observed fewer mtDNA heteroplasmic variants ({beta}=-3.2, p=0.026). Increased heteroplasmic variant load over time was also associated with older age ({beta}=1.50, p=0.001) and PD affection status ({beta}=5.0, p=1.0 x 10-4) in LRRK2 variant carriers. Notably, we observed distinct patterns of heteroplasmic variants that either increased or decreased in heteroplasmy level across passages. Conclusion: PacBio HiFi sequencing, combined with a single-amplicon strategy, enables accurate full-length mtDNA heteroplasmy detection and longitudinal analysis, providing a valuable tool for studying mitochondrial variation and dynamics in disease.