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01.
arXiv (CS.AI) 2026-06-25

ExTra: Exploratory Trajectory Optimization for Language Model Reinforcement Learning

arXiv:2606.24994v1 Announce Type: cross Abstract: Reinforcement Learning with Verifiable Rewards (RLVR) for language-model reasoning can fail at both extremes of task difficulty: easy prompts often produce all-correct, low-diversity rollout groups with little gradient signal, while hard prompts can produce all-incorrect groups with no positive reward. We introduce ExTra (Exploratory Trajectory Optimization), a GRPO-compatible framework that extracts exploration signals from the model's own rollouts. ExTra combines two mechanisms: (i) a novelty reward that adds embedding-based diversity bonuses after GRPO normalization, rewarding diverse correct solutions; and (ii) entropy-guided prefix regeneration, which scores partial trajectories using entropy signals and continues exploration from promising intermediate steps. Across six mathematical reasoning benchmarks, ExTra improves Qwen3-1.7B over GRPO by about +5 points on pass@1 and +7 points on pass@16, showing that trajectory-level exploration signals can improve both single-sample accuracy and inference-time coverage.

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

Toward the Whole Picture: Accumulative Fingerprint Mapping and Reconstruction for Small-Area Mobile Sensors

Small-area fingerprint sensing on mobile devices creates a fundamental mismatch between acquisition and recognition: each touch captures only a tiny, pose-varying local patch, while reliable biometric matching ultimately requires a stable and sufficiently complete fingerprint representation. Existing pipelines largely cope with this mismatch by treating repeated touches as independent partial templates, which leads to repeated registration, repeated matching, and no guarantee of adequate global coverage. In this paper, we advocate a different formulation, namely accumulative fingerprint mapping and reconstruction for small-area mobile sensing. Rather than matching every partial patch separately, the proposed perspective converts a sequence of local observations into a unified fingerprint state that is progressively refined as new touches arrive and can be matched only once after consolidation. As a concrete baseline, we present a classical pipeline that performs patch-wise structural feature extraction, feature-level registration and fusion, fingerprint map construction, and phase-based ridge reconstruction. More importantly, we position this baseline within a broader mobile fingerprint framework that integrates structured token learning, two-stage pose reasoning, and diffusion-based generative reconstruction. This viewpoint reframes mobile fingerprint recognition from multi-capture multi-match processing to accumulative map building, state refinement, and one-shot matching, offering a principled route toward efficient, pose-robust, and deployment-friendly biometrics for small-area mobile platforms. The baseline implementation has been publicly released at https://github.com/XiongjunGuan/FpReconstruction.

03.
arXiv (CS.CL) 2026-06-12

AI SciBrief as a Gateway to Research: A Framework for Onboarding Students into New Research Areas

Students at all levels of higher education face a significant barrier in the form of information overload, which often paralyzes the initial stages of the research process and suppresses motivation. In response, this article introduces a pedagogical framework that leverages AI SciBrief, a platform powered by a Large Language Model (LLM) designed to automatically generate digests of scientific trends. We describe how this multidisciplinary tool - with initial coverage in finance, medicine, and education - can be integrated into the curriculum to overcome this "entry barrier." The framework provides concrete methodologies for utilizing these digests to facilitate topic selection for term papers, accelerate literature reviews for dissertations, and enable postgraduate students to continuously monitor emerging trends. We conclude that AI SciBrief functions as a "gateway to research" effectively reducing students' cognitive load and empowering them to transition more rapidly from information searching to knowledge creation.

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

LLM-Powered AI Agent Systems and Their Applications in Industry

arXiv:2505.16120v3 Announce Type: replace Abstract: The emergence of Large Language Models (LLMs) has reshaped agent systems. Unlike traditional rule-based agents with limited task scope, LLM-powered agents offer greater flexibility, cross-domain reasoning, and natural language interaction. Moreover, with the integration of multi-modal LLMs, current agent systems are highly capable of processing diverse data modalities, including text, images, audio, and structured tabular data, enabling richer and more adaptive real-world behavior. This paper comprehensively examines the evolution of agent systems from the pre-LLM era to current LLM-powered architectures. We categorize agent systems into software-based, physical, and adaptive hybrid systems, highlighting applications across customer service, software development, manufacturing automation, personalized education, financial trading, and healthcare. We further discuss the primary challenges posed by LLM-powered agents, including high inference latency, output uncertainty, lack of evaluation metrics, and security vulnerabilities, and propose potential solutions to mitigate these concerns.

05.
arXiv (CS.AI) 2026-06-18

TLA-Prover: Verifiable TLA+ Specification Synthesis via Preference-Optimized Low-Rank Adaptation

arXiv:2606.06133v2 Announce Type: replace-cross Abstract: TLA+ is a formal specification language for verifying distributed systems and safety-critical protocols. Large language models (LLMs) frequently produce TLA+ specifications that fail the TLC model checker for semantic reasons. Across 25 LLMs, the best public baseline is 26.6% syntactic parse and 8.6% semantic model-check. We present TLA-Prover, a 20-billion-parameter model for TLA+ specification synthesis. Training combines supervised fine-tuning (SFT) on verified examples with repair-based group-relative policy optimization (GRPO). In the GRPO stage, the model learns to fix its own rejected specifications. We also train a direct preference optimization (DPO) variant from the same SFT checkpoint as an ablation. TLC provides the reward signal directly, with no learned reward model. Four tiers grade each output: Bronze (parses), Silver (no warnings), Gold (passes TLC), and Diamond. To reach Diamond, the model's correctness property is automatically altered in a small way; TLC must then detect a violation. If TLC still passes, the property was always-true and contributes nothing; the output fails Diamond. TLA-Prover reaches 9/30 (i.e. pass@1 = 30%) at both Gold and Diamond on a held-out 30-problem benchmark. This is roughly 3.5x the 8.6% untuned baseline. The DPO variant reaches 20% at Diamond. Gold and Diamond coincide at every checkpoint; this prevents the trivial-property failure mode.

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

Deep Neural Networks with Ordinal Loss for Medical Applications

arXiv:2606.25769v1 Announce Type: new Abstract: In many prediction problems in medical applications, target labels exhibit an inherent ordinal structure, where class ordering reflects clinically meaningful severity levels. The cost associated with misclassification is often non-uniform and asymmetric, as errors between distant ordinal categories may have substantially more severe consequences than errors between adjacent ones, and overestimating disease severity may have different clinical implications than underestimating it. Traditional loss functions such as multi-class cross-entropy treat all misclassifications equally and fail to incorporate this ordering information. Recent advances in ordinal regression aim to address this limitation by integrating rank-based structures into deep learning models. In this work, we introduce the Ordinal Cross-Entropy (OCE) framework, a general and architecture-independent approach for learning from ordinal data. The proposed method extends the standard cross-entropy formulation to account for misclassification severity through an ordinal cost matrix while preserving the probabilistic interpretation and optimization benefits of the conventional loss. We provide a theoretical analysis of the OCE gradient behavior and show that it yields smoother optimization dynamics and improved ordinal consistency. Experiments on benchmark datasets show that our method achieves lower prediction error costs and better calibration compared to existing state-of-the-art ordinal approaches, establishing OCE as a simple yet effective solution for ordinal regression in deep neural networks.

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

Timestep Rescheduling in Diffusion Inversion

Diffusion inversion, which maps images back to the Gaussian latent space of a diffusion model, is a critical task for image reconstruction and editing. While DDIM enables fast deterministic inversion, it inherently introduces deviations that accumulate into noticeable inversion errors. Existing methods often address this by solving a fixed-point problem but largely overlook how the selection of the diffusion timestep in the noise scheduler influences inversion fidelity. In this work, we reveal that the deviation scale in diffusion inversion is strongly dependent on the timestep size, and exhibits a parabolic trend, with larger errors concentrated at both small and large timesteps. Based on this finding, we propose a simple yet effective nonuniform timestep scheduler that integrates a global rescaling with a local dynamic programming based rescheduling, enabling a strategic allocation of computational effort that minimizes the overall inversion error and preserves higher inversion accuracy. Our method serves as an off-the-shelf enhancement for existing inversion techniques and requires no extra parameters or computational overhead. Through extensive experiments, we verify that integrating our scheduler consistently boosts the performance of existing inversion methods, achieving superior results in image reconstruction and editing.

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

Skill-Constrained Model Predictive Control for Resilient Manufacturing Supply Chains

arXiv:2606.17269v1 Announce Type: new Abstract: In skill-constrained production-inventory systems, the qualified human capacity available tomorrow depends on training decisions made today: production requires certified workers, certifications decay unless maintained, and training consumes the same scarce worker hours that production needs now. We study a closed-loop skill-constrained model predictive controller that, at every shift, solves a finite-horizon mixed-integer program over production, inventory, backlog, and training, with binary predicted certification, hard production eligibility, and an interpretable terminal value that prices certified-capacity gaps at the horizon boundary; only the first-period action is applied before replanning. On synthetic, seed-controlled SkillChain-Gym scenarios - announced and surprise new-skill shocks, demand shocks, absenteeism, forecast- and availability-quality modes, capacity-boundary and training-rate sweeps, and negative controls - we evaluate the controller against production-only and maintenance-only ablations, static cross-training insurance plans, and a strong reactive heuristic, under an ex-ante locked configuration and paired statistics. The result is regime dependence, not superiority: no policy class dominates. Predictive control helps when skill or labor bottlenecks are forecastable early enough for training to complete; lean static insurance remains hard to beat under surprise shocks, near the demand-capacity boundary, and wherever pre-shock slack makes insurance cheap. Attribution ablations separate certification maintenance, re-acquisition of lapsed certifications, and greenfield skill acquisition. Forecastability, not adaptivity per se, decides when predictive control pays.

09.
arXiv (CS.CL) 2026-06-12

Why Sampling Is Not Choosing: Intentionality, Agency, and Moral Responsibility in Large Language Models

Recent advances in large language models (LLMs) have prompted claims that such systems exhibit agency or qualify as moral agents. This paper argues that these attributions are misguided. We maintain that moral responsibility requires commitment-bearing agency grounded in intrinsic intentionality and self-attributed action, and that such agency constitutes the form of free will relevant to responsibility. Although LLMs generate coherent and normatively evaluable outputs, their operation is fully characterized by probabilistic input-output mappings learned from data. Their apparent intentionality is derived rather than intrinsic, and their outputs are neither owned as commitments nor guided by reasons. Variability introduced by stochastic sampling does not amount to choice or authorship. We address objections from the intentional stance, functionalism, compatibilism, and the presence of moral reasoning in model outputs, arguing that none suffice to establish genuine agency.

10.
arXiv (CS.AI) 2026-06-24

Alternate loss functions and regression models that achieve robustness to outliers by modulating the learning rate

arXiv:2606.22068v2 Announce Type: replace-cross Abstract: Most real-world datasets used for training supervised learning models are contaminated with noisy data and outliers leading to large prediction errors. This paper proposes a new approach for achieving robustness where the learning rate is modulated by a factor that is sensitive to outliers. In this approach a reduction of the learning rate is shown to be achieved by using alternate loss functions that are infinitely differentiable, strictly convex or quasiconvex and more closely approximate the absolute error than Huber and log-cosh losses. A comparison of the performance of regression models trained with different loss functions on a wide variety of benchmarks and datasets is presented to demonstrate the superior performance of the Square Root Loss (SRL) and Smooth Mean Absolute Error (SMAE) losses proposed in this paper. Two new robust linear regression models are presented. Highly vectorized robust parameter update formulae that take advantage of modern GPUs for both stochastic and batch gradient descent are presented.

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

Task-Aligned Stability Analysis of Vision-Language Models for Autonomous Driving Hazard Detection

Vision-language models (VLMs) are increasingly used for scene understanding in autonomous driving, but robustness analysis often relies on task-agnostic embedding stability alone. We study whether corruption-induced embedding drift predicts changes in a task-aligned hazard score derived from CLIP image-text similarities. Using controlled corruptions on BDD100K road scenes, we compare embedding drift against margin drift, defined as the change in hazard score under perturbation. The relationship is highly corruption-dependent: some families exhibit strong coupling between representation drift and decision drift, while others induce hazardous decision instability despite relatively modest embedding change. Furthermore, corruption families differ in failure direction: most suppress hazard detections via false negatives, while occlusion instead triggers false alarms, suggesting that benchmark design should account for asymmetric failure modes, not just overall instability rates. These results suggest that robustness benchmarks should include task-aligned stability measures in addition to embedding-level perturbation statistics.

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

A Knowledge Theory of Capital:The Value of Natural and Artificial Intelligence

arXiv:2606.18288v1 Announce Type: cross Abstract: This volume develops a knowledge theory of capital for economies in which productive capacity increasingly resides in software, data, models, routines, expertise, platforms, organizations, commons, and public epistemic infrastructure. Beginning from Adam Smith's theory of labour, stock, specialization, and market extent, it asks what changes when knowledge becomes stock-like, mobile across forms, scalable, governable, recombinable, and imperfectly visible in accounting. The book introduces knowledge-bearing stock as the central object and analyses how it is generated, converted into governable form, deployed, improved through feedback, enclosed or shared, measured, impaired, and used as input to future production. It distinguishes embodied, disembodied, institutionalized, commons, and public knowledge forms and develops concepts such as first conversion, cognitive enclosure, feedback capture, dark capital, and expected knowledge loss. The argument is conditional and testable: modern wealth depends not only on capital accumulation, but on how productive knowledge is governed.

14.
arXiv (CS.LG) 2026-06-25

The Geometry of Sequential Learning: Lie-Bracket Prediction of Transfer Order

作者:

arXiv:2606.24993v1 Announce Type: new Abstract: Sequential learning is order-dependent: from Pile-style next-token domain adaptation to instruction-SFT and DPO, N candidate sources induce N! possible curricula. We show that the local order effect is governed by a computable geometric quantity, the Lie-bracket commutator of gradient update fields, yielding a pairwise score for whether A->B or B->A is better for a target domain. The pairwise bracket primitive also defines a Lie-Bracket Tournament: with a shared theta_0 target-gradient reference, Hessian symmetry gives Borda/row-sum scores from one Hessian-vector product per source, O(N) dot products, and an O(N log N) sort, without materializing the O(N^2) edge matrix. Empirically, the planner reaches 98.1%/98.9% pairwise accuracy at k=1 for instruction-SFT/DPO, remains at 73.1%/72.2% at k=20, and preserves the original pretraining-domain evidence with 82.4-92.0% accuracy across four LLMs and 91.1% on diffusion. At curriculum scale, it recovers the best of all 3! schedules in 87.5% of trials, ranks 85 Stack programming-language source domains for a Python target in the 99th sampled percentile, and reaches the 99.0-99.6th sampled percentile on 56 MMLU subjects, sharply above the reported descending gradient-norm baseline. These results reframe sequential learning as a geometric tournament problem: commutators provide both local pairwise order information and a scalable primitive for many-domain schedules.

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

HRDX: A Large-Scale Vector HD-Map Dataset

Reliable autonomous driving requires vectorized HD maps that are geometrically accurate, semantically rich, and scalable to long-horizon driving. However, existing public HD map datasets are limited in scale, provide sparse semantic attributes, and lack modalities such as aerial imagery that could enable new research directions. We present HRDX, a large-scale dataset for vector HD-map construction, spanning about 40 hours (1,400 km) of minimally overlapping drives, which is several times larger than prior public HD map datasets. Data is captured using six synchronized surround cameras, a 128-beam LiDAR, and centimeter-level RTK GNSS/IMU, and is further complemented by precisely aligned aerial orthoimagery. Annotations cover 10 vector map classes, complemented with over 20 semantic and topological attributes. To evaluate this richer ontology, we introduce the Composite Score (CS) to jointly assess geometric fidelity and attribute correctness. Benchmark experiments show that HRDX's scale improves online vector-map construction, and that aligned aerial imagery provides a useful structural prior: using aerial imagery at training and/or inference improves geometric map quality, while aerial-augmented teachers can transfer part of this benefit to camera-only students without increasing inference-time sensor requirements. HRDX is intended to support reproducible research on large-scale HD-map learning, multimodal BEV fusion, and training-time privileged information. HRDX dataset and benchmarks are available at https://github.com/honda-research-institute/HRDX

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

Anti-causal domain generalization: Leveraging unlabeled data

arXiv:2602.17187v2 Announce Type: replace-cross Abstract: The problem of domain generalization concerns learning predictive models that are robust to distribution shifts when deployed in new, previously unseen environments. Existing methods typically require labeled data from multiple training environments, limiting their applicability when labeled data are scarce. In this work, we study domain generalization in an anti-causal setting, where the outcome causes the observed covariates. Under this structure, environment perturbations that affect the covariates do not propagate to the outcome, which motivates regularizing the model's sensitivity to these perturbations. Crucially, estimating these perturbation directions does not require labels, enabling us to leverage unlabeled data from multiple environments. We propose two methods that penalize the model's sensitivity to variations in the mean and covariance of the covariates across environments, respectively, and prove that these methods have worst-case optimality guarantees under certain classes of environments. Finally, we demonstrate the empirical performance of our approach on a controlled physical system and a physiological signal dataset.

17.
arXiv (quant-ph) 2026-06-11

Clifford disentanglers for entanglement reduction in molecular electronic structure simulations

arXiv:2606.12056v1 Announce Type: new Abstract: Entanglement is a key bottleneck limiting the efficiency of tensor-network and quantum simulations of molecular electronic structures. Here, we systematically assess and extend Clifford disentanglers as a structure-preserving approach to entanglement reduction: they can modify the entanglement structure of qubit wavefunctions while retaining the Pauli-string form of qubit Hamiltonians. To enable a practical search over Clifford transformations, we classify Clifford operators by their action on the Schmidt spectrum across a bipartition, reducing the two- and four-qubit search spaces to 20 and 91392 representatives, respectively. Embedded in an iterative Clifford-augmented matrix product state framework, these transformations reduce the energy errors at fixed bond dimension for the molecular test cases studied and mitigate the dependence on orbital orderings and fermion-to-qubit mappings. We further show that Clifford disentanglers can also benefit quantum simulations such as the shallow-circuit variational quantum eigensolver calculations. Together, these results establish Clifford disentanglers as a useful structure-preserving entanglement-engineering tool for tensor-network and quantum simulations of molecular electronic structure, while also clarifying their correlation dependence and motivating future developments.

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

FlowBender: Feedback-Aware Training for Self-Correcting Conditional Flows

Conditional diffusion and flow models routinely fail to satisfy the very constraints that define their task. For instance, a depth-conditioned model often produces images whose re-extracted depth disagrees with the input, even though the forward operator–the depth predictor defining the constraint–is available during both training and inference. Existing approaches generally fall into two categories: supervised models that treat the conditioning signal as a static cue and ignore alignment information at inference, and guidance-based methods that consult it through hand-tuned linear updates, typically trading fidelity to the condition against the plausibility of the generated sample. We argue that the fundamental gap in both paradigms is that the model is never trained to utilize its own alignment error. We introduce FlowBender, a closed-loop framework that treats this error as a first-class input, training the network to learn a correction policy conditioned on inference-time feedback. At each step, an unguided look-ahead pass estimates the clean signal, a task-specific deviation is computed via the forward operator, and a refinement pass consumes this signal to produce a corrected velocity. We propose several variants of FlowBender, including a gradient-based formulation for differentiable operators and a zero-order variant for non-differentiable settings such as JPEG compression. For efficient sampling, we introduce a prior-step shortcut that enables closed-loop correction at a minimal additional computational cost. Across image-to-image translation, restoration, and 3D mesh texturing, FlowBender consistently outperforms standard supervised baselines, alignment-loss-augmented training, and state-of-the-art inference-time guidance, improving fidelity and plausibility simultaneously rather than trading them against each other. Project page: https://flow-bender.github.io/

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

A Controlled Benchmark of Quantum-Latent GAN Augmentation for Brain MRI

Medical image classification is often constrained by limited labeled data, motivating generative augmentation; recently, quantum generative models have been proposed for this purpose, frequently reporting accuracy gains. However, such claims are typically based on single training runs, do not match the parameter budgets of the quantum and classical generators, and do not characterize the data regime in which any benefit appears. We present a controlled benchmark that isolates the contribution of a quantum generator to brain-MRI augmentation. Images are encoded into a KL-regularized latent space in which a conditional Wasserstein GAN with gradient penalty is trained using either a variational quantum generator or a classical generator of near-identical parameter count (1648 vs. 1632). Synthetic samples are decoded and used to augment a pretrained classifier across labeled data fractions from 5% to 100%, evaluated over eight random seeds with paired significance testing (with multiple-comparison correction) and with intraset diversity and latent-distribution analyses. Across all fractions, no augmentation variant significantly outperforms real-data-only training, and the quantum and classical generators are statistically indistinguishable. Any low-data benefit behaves as regularization rather than faithful data expansion:synthetic samples are off distribution and severely mode collapsed precisely where data is scarce, and the quantum generator is no more diverse thanits classical counterpart. We release the protocol as a testbed for rigorous evaluation of quantum generative augmentation in medical imaging.

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

DP-Hype: Federated Differentially Private Hyperparameter Search

arXiv:2510.04902v3 Announce Type: replace Abstract: Tuning hyperparameters in federated machine learning can substantially impact model performance. When hyperparameters are tuned on sensitive data, privacy becomes an important challenge and to this end, differential privacy has emerged as the de facto standard for provable privacy. A standard setting in federated learning is that clients agree on a shared setup, i.e., find a compromise from a set of hyperparameters, like a model's learning rate. Yet, prior work on privacy-preserving hyperparameter tuning is tailored to specific learning tasks, does not account for the privacy leakage of aggregated results, or offers a sub-optimal privacy-utility trade-off. In this work, we present our algorithm DP-Hype, which performs a federated and privacy-preserving hyperparameter search by conducting a federated voting based on local hyperparameter evaluations of clients. In this way, DP-Hype selects hyperparameters that lead to a compromise supported by a majority of clients, while maintaining scalability and independence from specific learning tasks. We prove that DP-Hype preserves the strong notion of differential privacy called client-level differential privacy and, importantly, show that its privacy guarantees do not depend on the number of hyperparameters. We also provide bounds on its utility guarantees, that is, the probability of finding good hyperparameters, and implement DP-Hype as a submodule in the popular Flower framework for federated machine learning. In addition, we evaluate performance on multiple benchmark data sets in iid as well as multiple non-iid settings and demonstrate high utility of DP-Hype even under small privacy budgets.

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

GauS: Differentiable Scheduling Optimization via Gaussian Reparameterization

arXiv:2602.20427v2 Announce Type: replace Abstract: Efficient operator scheduling is a fundamental challenge in software compilation and hardware synthesis. While recent differentiable approaches have sought to replace traditional ones like exact solvers or heuristics with gradient-based search, they typically rely on categorical distributions that fail to capture the ordinal nature of time and suffer from a parameter space that scales poorly. In this paper, we propose a novel differentiable framework, GauS, that models operator scheduling as a stochastic relaxation using Gaussian distributions, which fully utilize modern parallel computing devices like GPUs. By representing schedules as continuous Gaussian variables, we successfully capture the ordinal nature of time and reduce the optimization space by orders of magnitude. Our method is highly flexible to represent various objectives and constraints, which provides the first differentiable formulation for the complex pipelined scheduling problem. We evaluate our method on a range of benchmarks, demonstrating that Gaus achieves Pareto-optimal results.

22.
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.

23.
Nature (Science) 2026-06-24

Immunological mechanisms of mRNA vaccines for infectious diseases

Nucleoside-modified mRNA–lipid-nanoparticle (mRNA–LNP) vaccines confer a high level of protection against severe COVID-19 and, since their first authorization for human use in 2020, have saved millions of lives. The efficacy of this vaccine platform relies on the induction of powerful and coordinated innate and adaptive immune responses. A deep understanding of the mechanisms of action by which mRNA–LNP vaccines drive protective immunity is crucial for advancing the development of next-generation mRNA vaccines with improved immunogenicity and tolerability. A flurry of recent studies has shed light on aspects of this vaccine modality’s modus operandi. Nonetheless, key gaps in knowledge remain, including understanding how LNPs are sensed by the immune system and exert their adjuvant activity, identifying the specific signals and cellular pathways critical for eliciting protective immune responses and determining whether it is feasible to uncouple vaccine immunogenicity and reactogenicity. Here we review the known and unknown features of the immunological mechanisms of mRNA–LNP vaccines for infectious diseases. Furthermore, we discuss how the components of this vaccine platform can be modified to fine-tune immune responses against challenging pathogens for which effective vaccines do not exist or need improvement. A Review of the immunological mechanisms of mRNA–lipid-nanoparticle vaccines for infectious diseases discusses how the components of this vaccine platform can be modified to fine-tune immune responses against challenging pathogens.

24.
arXiv (CS.AI) 2026-06-25

Stabilizing black-box algorithms through task-oriented randomization

arXiv:2606.25269v1 Announce Type: cross Abstract: As black-box models become foundational to modern research, ensuring their stability is paramount for the realization of trustworthy artificial intelligence. The inherent diversity of inputs - ranging from structured Gaussian distributions to complex data with unknown structures - poses a significant challenge: how to stabilize black-box outputs while effectively leveraging available prior information. This paper introduces a task-oriented randomization methodology that adaptively tailors its strategy to the underlying generative mechanisms of the input data, specifically addressing unstructured complexities. A comprehensive suite of stability guarantees is proposed. Beyond establishing rigorous theoretical foundations for stability, the research provides a detailed analysis of the intrinsic trade-off between stability and exploration. Motivated by the architecture of Large Language Models, the framework is further extended to top-k ranking problems. The validity and effectiveness of the proposal are demonstrated through extensive numerical simulations and applications to the real-world dataset.

25.
arXiv (quant-ph) 2026-06-16

How Many Shots Are Enough for a Quantum Circuit?

arXiv:2606.16965v1 Announce Type: new Abstract: Quantum algorithms require repeated circuit executions, known as shots, to estimate output distributions accurately. Determining the minimal number of shots needed to meet a target accuracy is crucial to reduce costs and resource usage, especially on today's noisy and expensive quantum hardware. In this paper, we address the shot optimisation problem in a black-box setting, where no assumptions are made about the structure of the quantum circuit or the noise model of the backend. We introduce IncrementalExecution, a novel online framework that dynamically determines when to stop executing shots based on the principle of point of diminishing returns: the point at which additional shots no longer significantly alter the empirical distribution of a fixed circuit. The framework supports customisable policies for shot management, enabling flexible trade-offs between execution cost and result fidelity within static execution scenarios. We assess our proposal through an extensive experimental evaluation spanning 33,750 framework configurations across 180 unique static quantum circuit-backend combinations, for a total of 7.3M independent experiments. Unlike prior work that relies on problem-specific knowledge or algorithm-dependent assumptions (e.g., variational or adaptive workflows), our approach is applicable to a large set of static circuits and immediately deployable on current quantum cloud platforms.