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01.
Nature (Science) 2026-06-17

The EU needs to back its ambition to end animal testing with cash

作者: 未知作者

The European Union has declared that it wants to stop using animals in chemical safety testing. Its goal will need a timeline and a serious funding commitment. The European Union has declared that it wants to stop using animals in chemical safety testing. Its goal will need a timeline and a serious funding commitment.

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

SCAR: Semantic Continuity-Aware Retrieval for Efficient Context Expansion in RAG

Fixed-length chunking in Retrieval-Augmented Generation (RAG) often leads to boundary fragmentation, where critical evidence is split across segments, degrading retrieval recall. While static windowing and parent retrieval improve recall, they introduce significant token overhead. We propose SCAR (Semantic Continuity-Aware Retrieval), an adaptive retrieval policy that selectively expands neighboring chunks by weighing query-neighbor relevance against a structural continuity penalty. SCAR uses a relative expansion threshold tied to each retrieved chunk's own query-relevance, yielding an approximately scale-invariant decision rule that transfers across embedding models without recalibration. Across four diverse corpora (RFC, GDPR, a 10-K report, and a Merger agreement; N=320 queries; 160 boundary-fragmented), SCAR achieves 92.8% recall on boundary-fragmented queries with only 7.84 chunks, a 22.9% reduction compared to static windowing (10.16 chunks). Paired bootstrap tests (B=10,000) confirm the chunk reduction is highly significant (p

03.
arXiv (CS.AI) 2026-06-15

CARE: Controlling LLM-Generated Policies through Auditable Review of Evidence in Scientific Experimentation

arXiv:2606.14581v1 Announce Type: cross Abstract: Granting LLMs direct control over costly, irreversible scientific experiments leads to unsafe exploration and unstable performance, but discarding LLM creativity entirely sacrifices significant optimization potential. We introduce CARE (Controlling LLM-Generated Policies through Auditable Review of Evidence in Scientific Experimentation), an auditable controller for high-throughput experimentation (HTE) optimization that keeps a non-LLM incumbent optimizer as the default action path while using LLMs to revise challenger ranking policies. Before each outcome is revealed, a public-evidence intervention gate compares the challenger with the incumbent. It authorizes the challenger's selection only when the evidence available before selection supports the change, with the decision recorded in the audit log. CARE outperforms all other evaluated methods on Minerva/Olympus and ChemLex benchmarks, with final-best improving from 80.0 to 88.5 on Minerva/Olympus and from 83.9 to 92.1 on ChemLex, relative to the public incumbent. Our experiments indicate that LLM self-evolution is more reliable when it expands the proposal space under an auditable controller, rather than directly choosing experiments.

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

VideoSketcher: Sequential Sketch Generation Using Video Model Priors

Sketching is inherently sequential: strokes are drawn progressively to explore and refine ideas. Yet most generative approaches treat sketches as static images, ignoring the temporal process underlying creative exploration. Modeling this sequential structure remains challenging: prior methods either rely on large-scale human-drawn datasets with limited diversity, or use large language models (LLMs) to produce drawing instructions, often at the cost of visual fidelity. We present VideoSketcher, a method for generating high-quality sketching processes by adapting pretrained text-to-video diffusion models to the sparse, continuous nature of sketch formation. Our key insight is that LLMs and video diffusion models offer complementary strengths: LLMs act as semantic planners that decompose concepts into step-by-step instructions, while video diffusion models serve as powerful "renderers" that translate them into temporally coherent sketch sequences. We introduce a two-stage fine-tuning strategy that decouples temporal structure from visual appearance: stroke ordering is learned from synthetic shape compositions, while style is distilled from as few as seven hand-drawn examples. Despite minimal supervision, our method can generate diverse, high-quality sequential sketches that faithfully follow specified drawing orders. Our framework naturally extends to brush style control and autoregressive generation, supporting artistic applications.

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

GridVQA-X: A Framework for Evaluating Multimodal Explainability Methods

With the increasing development of Vision-Language Models, it becomes imperative that their predictions are readily explainable to relevant stakeholders. However, the field of explainability has not kept pace with the multimodal surge. While recent Multimodal Explainable AI (MxAI) methods generate explanations to attribute the interaction between different modalities, current evaluation protocols lack the ground truth required to distinguish between true cross-modal reasoning (e.g., spatial composition) and shallow cross-modal shortcuts (e.g., Bag-of-Words attribute matching). It remains unknown whether MxAI methods faithfully capture synergistic interactions or merely hallucinate reasoning on models acting as simple feature detectors. In this paper, we introduce GridVQA-X, the first diagnostic framework specifically designed to evaluate cross-modal explainability. Unlike natural datasets, GridVQA-X leverages a closed-world synthesis logic to generate unique, mathematically guaranteed explanations. We utilize this controlled environment to train paired ground-truth models on identical architectures: $M_{pure}$, which learns robust spatial-relational reasoning and $M_{spur}$, which is structurally forced to rely on cross-modal shortcuts. This behavioral divergence creates a rigorous testbed: a faithful explainer must report distinct reasoning pathways for each model. Our findings reveal that widely used methods fail to distinguish between models relying on genuine spatial-relational reasoning and those exploiting cross-modal shortcuts, highlighting a critical gap in capturing true cross-modal synergy and misrepresenting how multimodal models actually make decisions.

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

AI Sandboxes: A Threat Model, Taxonomy, and Measurement Framework

arXiv:2606.18532v1 Announce Type: cross Abstract: AI systems are increasingly evaluated in bounded environments that combine isolation, simulation, instrumentation, supervision, and evidence capture. For physical AI, AIoT, and cyber-physical systems, this shift is not a matter of terminology: the system under test may sense, decide, actuate, communicate, and fail through physical processes, networked devices, and human operators. This article develops an assurance-oriented account of AI sandboxes as controlled environments for testing, evaluation, verification, and validation across digital AI, embodied autonomy, and cyber-physical deployments. We formalize the sandbox boundary and a weakest-link rule for composing per-dimension evidence into a bounded deployment claim; separate major sandbox archetypes; define a cyber-physical threat model that includes attacks on the assurance apparatus itself; and introduce a measurement framework spanning fidelity, controllability, observability, containment, reproducibility, and governance artifacts, instantiated on three worked case studies of real sandboxes. The resulting threat model, taxonomy, and measurement framework clarify what a sandbox can validly test, which risks it can contain, and what forms of evidence it can support for safety, security, and regulatory assurance.

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

HypOProto: Hyperbolic Ordinal Prototypes for Left Ventricular Filling Pressure Classification

Echocardiography (echo) is a widely used imaging modality for assessing cardiac function, with Left Ventricular Filling Pressure (LVFP) serving as a critical physiological marker for conditions such as heart failure. Standard LVFP classification into normal vs elevated categories relies on the Doppler-derived $E/e'$ ratio, which is operator-dependent and often unavailable in resource-limited settings, motivating methods that infer LVFP directly from B-mode echo. Existing deep learning approaches achieve high performance but remain largely black-box, limiting clinical interpretability. We propose HypOProto, a hyperbolic, ordinal prototype-based framework for interpretable LVFP classification using a frozen, explainable foundation model backbone. HypOProto arranges prototypes along the physiological $E/e'$ scale, placing borderline cases near the hyperboloid root where small angular differences separate similar cases, while normal and elevated cases occupy outward positions reflecting increasing diagnostic certainty. This hyperbolic geometry encodes clinically meaningful ordinal relationships and improves interpretability. We also introduce a novel Hyperbolic Prototype Angular Separation (HyperPAS) loss, enforcing inter-class prototype separation in hyperbolic space. HypOProto achieves SOTA performance while maintaining transparency, and highlights clinically relevant regions in visualizations. This work represents the first prototype-based framework for LVFP classification in echo. Our code can be found at https://github.com/DeepRCL/HypOProto.

08.
arXiv (math.PR) 2026-06-16

Atypical Decay Rates for Atypical Heights in Random Recursive Trees

arXiv:2604.20139v2 Announce Type: replace Abstract: We establish the large deviation probabilities for the height of random recursive trees, revealing polynomial upper-tail decay and stretched-exponential lower-tail decay. Remarkably, the lower tail features an atypical prefactor that grows to infinity more slowly than any $n$-fold iterated logarithm.

09.
arXiv (CS.CV) 2026-06-16

Object Tokens as a Bridge Between Segmentation and Visual Question Answering in Robotic Surgery

Visual Question Answering (VQA) in robotic surgery, referred to as surgical VQA, requires high-level understanding of complex surgical scenes and the integration of visual perception with language reasoning, with the potential to support surgical training and intraoperative decision-making. Recent Vision-Language Models (VLMs) have shown promising performance through parameter-efficient fine-tuning; however, most existing approaches rely on coarse visual grounding, typically limited to bounding boxes, which fails to capture the fine-grained spatial structure of surgical objects. In this work, we propose a unified framework that jointly performs pixel-level segmentation and visual question answering within a single framework. Our approach integrates a VLM with a Segment Anything Model (SAM)-based decoder and represents scene elements as object tokens generated by the VLM. These object tokens guide answer prediction and are further projected to the SAM-based decoder to produce segmentation masks. By optimizing the object token embeddings through both segmentation and question answering objectives, the model learns spatially grounded representations that enhance visual reasoning while providing explicit pixel-level grounding. We evaluate the proposed method on the private RAMIE (Robot-Assisted Minimally Invasive Esophagectomy) dataset and the public EndoVis18 dataset, where it consistently outperforms baseline methods for surgical VQA. These results demonstrate that incorporating context-aware object tokens into vision-language models improves fine-grained surgical scene understanding.

10.
arXiv (CS.AI) 2026-06-19

ZeSTA: Zero-Shot TTS Augmentation with Domain-Conditioned Training for Data-Efficient Personalized Speech Synthesis

arXiv:2603.04219v2 Announce Type: replace-cross Abstract: We investigate the use of zero-shot text-to-speech (ZS-TTS) as a data augmentation source for low-resource personalized speech synthesis. While synthetic augmentation can provide linguistically rich and phonetically diverse speech, naively mixing large amounts of synthetic speech with limited real recordings often leads to speaker similarity degradation during fine-tuning. To address this issue, we propose ZeSTA, a simple domain-conditioned training framework that distinguishes real and synthetic speech via a lightweight domain embedding, combined with real-data oversampling to stabilize adaptation under extremely limited target data, without modifying the base architecture. Experiments on LibriTTS and an in-house dataset with two ZS-TTS sources demonstrate that our approach improves speaker similarity over naive synthetic augmentation while preserving intelligibility and perceptual quality. Audio samples are available on our web page.

11.
arXiv (quant-ph) 2026-06-12

Robust Pretty Good Measurement via Hybrid Classical-Quantum Pseudoinverse Approximation and Circuit-Level Realization

arXiv:2606.13150v1 Announce Type: new Abstract: Pretty Good Measurement (PGM) is a near-optimal strategy for quantum state discrimination, but its practical realization becomes unstable when the ensemble operator is singular or ill-conditioned. We introduce a numerically robust PGM formulation based on the Moore-Penrose pseudoinverse, replacing the standard inverse square root with a threshold-regularized variant that remains well-defined across different spectral regimes. We develop a hybrid classical-quantum framework that combines pseudoinverse-based spectral preprocessing with quantum circuit realizations using block-encoding and spectral-transformation techniques. The framework incorporates support awareness, yielding physically meaningful measurement operators even in rank-deficient cases, and employs oblivious amplitude amplification to improve circuit-level success probabilities. Extensive numerical and circuit-level simulations show close agreement between theoretical predictions and quantum circuit outputs. Experiments on synthetic and real datasets, including ill-conditioned and degenerate scenarios, demonstrate stable discrimination performance where standard PGM becomes numerically unstable. The results establish a practical hybrid classical-quantum framework for robust quantum state discrimination and extend previous circuit-based implementations of the PGM testing stage toward pseudoinverse-aware measurement design.

12.
bioRxiv (Bioinfo) 2026-06-18

Bayesian modeling of longitudinal metatranscriptomes of broiler meat spoilage microbiomes shows shared predictive signature associated with spoilage at refrigerated temperatures

Microbial spoilage of packaged meat is driven by complex microbial succession and related metabolic activity, yet conventional shelf-life assessment is mainly based on shelf-life studies relying on culturing and sensory analysis. In routine quality assurance, results are obtained retrospectively, and they are only indirectly linked to the metabolic activity related to sensory deterioration. Functional, time informative approaches that capture the active metabolic state of the spoilage microbiome and predict the rate of spoilage are lacking. We developed a censoring-aware Gaussian process (CAGP) framework to model longitudinal pathway expression profiles from broiler meat metatranscriptomes collected over consecutive storage days at 4 or 6{degrees}C. Samples were annotated using odor-based sensory scores defining fresh, early-spoilage, and late-spoilage phases. Because observed zeros in pathway-level data may reflect non-detection rather than true absence, the model treats low values as left-censored observations below a detection threshold while estimating smooth temporal trajectories with uncertainty. In leave-one-out prediction within the 4{degrees}C time series, predicted sampling days differed from the true days by an average of 0.43 days, and predicted spoilage phases agreed with the sensory classification. Trajectories learned at 4{degrees}C also transferred to an independent 6{degrees}C time series at the spoilage-phase level, suggesting that shared functional spoilage programs are preserved despite temperature-dependent changes in spoilage rate. Cross-entropy ranking further identified pathway modules carrying time- and phase-informative signals across temperatures. Overall, this framework provides a probabilistic approach for linking metatranscriptomic functional dynamics to sensory spoilage progression, supporting shelf-life assessment beyond retrospective microbial enumeration.

13.
arXiv (CS.LG) 2026-06-15

Code Correctness Signals in LLM Hidden States: Pre-Generation Probing and Repair Geometry

arXiv:2606.14530v1 Announce Type: new Abstract: Large language models encode rich information in their hidden states. This work asks whether code correctness is legible in the hidden states of Qwen3-4B-Instruct-2507, before it generates and as it repairs a failed attempt, studied on 444 LiveCodeBench tasks. It reports two findings connected by a single confound-control tool: residualization. First, the correctness of the model's first-attempt code is linearly decodable from the prompt-final hidden state, with a leakage-free held-out AUC of 0.931 +/- 0.008 across 50 outer splits. After the linear effect of prompt length is removed from each hidden state dimension, the probe still reaches 0.911 +/- 0.010, well above a prompt-length baseline of 0.754 +/- 0.014. Second, on 236 cleaned cases where the model attempts to repair a failed first attempt, the hidden state shift from the failing attempt to its repair carries a statistically detectable contrastive direction, significant on both a magnitude and a split-half test against label-shuffled nulls. This direction does not survive a conditional residualization against repair-context covariates that differ between successful and failed repairs, marking it as a correlate of repair success driven by the repair context rather than an isolated repair-comprehension feature. The probe layer is selected by nested cross-validation, and the same residualization approach that upholds the pre-generation correctness result overturns the repair-direction interpretation. The contribution is as much methodological as empirical: a diagnostic honest enough to report a negative result alongside a positive one.

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

Entity Binding Failures in Speech LLM Reasoning: Diagnosis and Chain-of-Thought Intervention

Speech Large Language Models (SLLMs) underperform their text counterparts on complex reasoning. We reveal that this gap is not a uniform cognitive deficit. Evaluating two architecturally diverse SLLMs, we show speech-to-text (S2T) matches or exceeds text-to-text (T2T) on spatial, syntactic, and factual tasks. Yet on logical tasks requiring entity tracking, S2T accuracy collapses to chance. We diagnose this as an entity binding failure: continuous speech features blur precise entity-property associations during implicit reasoning. To validate this diagnosis, we introduce Entity-Aware Chain-of-Thought (EA-CoT), a lightweight inference-time intervention forcing SLLMs to enumerate entities and bind them to claims before reasoning. EA-CoT bridges the gap, even when spoken names are misrecognized, yielding up to a 24.4 percentage-point accuracy gain. Ablations confirm the gains stem from explicit semantic binding, reframing the gap as an elicitation failure rather than a missing capability.

15.
arXiv (CS.LG) 2026-06-18

A physical adaptive material motor unit neural network: a hygromorph composite material machine

arXiv:2606.18275v1 Announce Type: cross Abstract: Advances in novel materials science enable structures to function as intelligent machines by embedding memory and learning capabilities directly into materials. Our work introduces a physical adaptive material motor unit neural network,leveraging a new generation of controllable actuators composed of wood- and carbon black-based composites, sensitive to temperature and relative humidity. These material actuators are assembled into a motor unit-like structure inspired by muscle contraction trigger, forming an intelligent machine capable of dynamic shading control that can be used, for example, in buildings. The machine is governed by a neural network trained on over 350 experimental data points collected under diverse environmental conditions. By establishing a new data-aware backpropagation training, we show that the machine predicts shading responses and learns to predict appropriate behaviour incrementally as the database expands. We also demonstrate the ability of the machine to optimise configurations to achieve similar shading outputs under two distinct conditions.

16.
arXiv (quant-ph) 2026-06-11

Strong-field control of the $Z$-boson resonance in $e^+e^-$ collisions

arXiv:2606.09394v2 Announce Type: replace-cross Abstract: Resonant $Z$-boson production is a cornerstone of precision electroweak physics, with its vacuum line shape set by the $Z$ mass, width, and collision kinematics. We show that a strong laser field can significantly alter this picture. By treating the field nonperturbatively, we find that laser dressing of the incoming fermions alters the effective collision kinematics and opens laser-photon exchange channels, including multiphoton processes, in $e^{+}e^{-}$ collisions. As a result, the $Z$-resonance profile develops distinct intensity-dependent regimes, evolving from the vacuum limit to saturation at intermediate field strengths and to an approximately quadratic enhancement at higher intensities. Additionally, the polarization composition of the produced $Z$ bosons is redistributed. In particular, at high intensities the laser-induced contribution can compensate the intrinsic chiral asymmetry of the electroweak interaction, leading to nearly parity-balanced $Z$-boson production. Our results identify that strong classical fields can dynamically control electroweak resonance phenomena, opening a bridge between strong-field QED and high-energy collider physics.

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

BiWM: Advancing Open-Source Interactive Video World Models with Bidirectional Autoregression

Transitioning bidirectional video diffusion models into an autoregressive paradigm improves the interactivity of video world models, but existing causal pipelines need many stages (control fine-tuning, autoregressive training, causal initialization, few-step distillation) and still trail bidirectional models in quality due to error accumulation. Recent world models such as Yume-1.5 and Matrix-Game-3.0 instead adopt a bidirectional autoregressive approach, gaining fidelity and stable long-horizon rollout from self-correcting error propagation, yet open-source frameworks (e.g., minWM) support only causal models. We present BiWM, the first full-stack framework for interactive video world models under the bidirectional autoregressive paradigm, jointly optimizing generation quality and inference speed. From a pretrained video backbone, BiWM injects camera control by fine-tuning, then runs a few-step Distribution Matching Distillation (DMD) stage that turns the backbone into an action/camera-controllable world model: just two training stages instead of four in minWM, converging in a few hundred steps on 8xH200 GPUs. A single recipe spans Wan2.1-1.3B, Wan2.2-5B, HunyuanVideo-1.5-8B, and LTX-2.3-22B, and also supports secondary fine-tuning of existing bidirectional models. BiWM enables real-world camera control where minWM loses controllability, integrates pluggable history compression (FramePack-style and PackForcing-style) for long rollouts, and offers an optional NVFP4 4-bit training/inference pipeline. To counter DMD's mode-seeking degradation, we add GAN and mass-covering forward-KL objectives that preserve scene dynamics. We open-source BiWM for resource-constrained research and high-fidelity environment simulation.

18.
medRxiv (Medicine) 2026-06-17

Efficacy of a Gamified Digital Platform for Substance Use Education and Overdose Prevention Among College Students: a Pilot and Feasibility Study

Background: For US young adults aged 18-25 in the 2018-2024 period, fentanyl was involved in 78.2% of the 44,020 unintentional or undetermined-intent overdose deaths, most often co-involving stimulants and other non-opioid substances. While fatal overdose rates in this age group have fallen to their lowest recorded level, emergency medical services-attended non-fatal overdose events have reached record highs, shifting the decisive variable toward bystander recognition and response. College students report near-universal alcohol education but minimal education on the substances actually driving overdose mortality. Methods: We conducted a single-group pre-post evaluation of the DopaGE Portal, a gamified, mastery-based digital platform covering cocaine, MDMA, benzodiazepines, and opioid overdose response, deployed at a public university (UNL) and a multi-campus volunteer network (TACO). Paired pre/post surveys (N=42) measured self-efficacy (7 items; primary), behavioral intentions, risk perception, and knowledge/attitudes on 5-point scales, plus four factual knowledge questions. Paired t-tests, exact McNemar tests, and Benjamini-Hochberg correction across eight primary tests were applied. Institutional naloxone distribution at UNL was tracked as an ecological behavioral outcome. A mandated high-school cohort (N=94) provided supplementary acceptability data. Results: Self-efficacy increased from 2.82 to 4.46 (d=2.00, 95% CI 1.46-2.55; adjusted p

19.
arXiv (CS.AI) 2026-06-11

Libra: Efficient Resource Management for Agentic RL Post-Training

arXiv:2606.03077v2 Announce Type: replace-cross Abstract: Reinforcement learning (RL) has emerged as a standard post-training paradigm for shaping large language models (LLMs) into capable agents. In agentic RL, the rollout stage generates trajectories while invoking tools, producing long-tailed and non-stationary workloads that expose two fundamental challenges in resource management. First, due to the long-tail distribution, a small fraction of trajectories dominates rollout makespan. Second, rollout and training are subject to cross-stage imbalance, as they exhibit strong asymmetry in compute patterns, memory demands, and sensitivity to sequence length. Compounding this asymmetry, the sequence length distribution drifts continuously as the policy evolves, rendering any static resource split progressively suboptimal. We present Libra, a resource management system to address both challenges via two core mechanisms. The first is a global resource planner that jointly optimizes GPU allocation across rollout and training clusters. It leverages an elastic hybrid pool to enable lightweight, non-blocking worker reallocation between stages. The second is a causality-driven multi-level feedback queue (C-MLFQ) scheduler, which routes requests to heterogeneous rollout buckets based on causal signals derived from tool-return outcomes, rather than relying on fragile length predictions. Evaluated on 48 A800 GPUs, Libra achieves up to 3.0x higher throughput and converges up to 2.5x faster in reward compared to the baselines.

20.
arXiv (CS.AI) 2026-06-15

STaR-DRO: Stateful Tsallis Reweighting for Group-Robust Structured Prediction

arXiv:2604.09737v2 Announce Type: replace-cross Abstract: Structured prediction with large language models requires outputs that are label-accurate, ontology-constrained, structurally valid, and evidence-grounded under label imbalance and heterogeneous group difficulty. We present a unified framework for ontology-constrained generation. First, we introduce a modular prompt-engineering architecture combining XML-style structure, expert disambiguation rules, chain-of-thought reasoning, metadata-aware decision logic, schema contracts, and a self-validation gate. It targets recurrent in-context failures, including format drift, label ambiguity, evidence hallucination, and metadata-conditioned confusion. Second, we propose STaR-DRO, combining Tsallis mirror ascent, sparse entmax-style primal mapback, EMA-smoothed group-loss tracking, rescaled ascent signals, and bounded excess-only multipliers. Unlike conventional DRO, which relies on dense Shannon-entropy exponentiated-gradient updates, can introduce high-variance stochastic reweighting, assigns positive adversarial mass to groups that are not persistently hard, and incurs costs through simplex competition, STaR-DRO upweights only persistently hard groups without suppressing easier ones. We evaluate the framework on EPPC Miner, a clinically grounded high-stakes structured-prediction task requiring hierarchical label prediction and evidence-span extraction from patient-provider secure messages. Across 1B-70B Llama models, prompt engineering improves zero-shot extraction, yielding an average label F1 gain of +14.46 and a Span F1 gain of +17.40. Building on supervised fine-tuning, STaR-DRO further improves accuracy and robustness, increasing average label F1 by +1.08 and +2.20 while reducing mean groupwise validation cross-entropy by 21.3% and 14.8% relative to SFT and standard DRO, respectively. These results advance reliable automated communication mining for patient-centered clinical care analysis.

21.
medRxiv (Medicine) 2026-06-19

Reassessing Instrument Strength in Two-Sample Mendelian Randomization Analysis

Mendelian randomization (MR) analysis is widely used to estimate causal relationships between risk factors and outcomes of interest. Two-sample MR approaches have gained increasing attention in genetic epidemiology due to the growing availability of Genome-Wide Association Study (GWAS) summary statistics from public databases. A critical step in two-sample MR is the selection of genetic variants as instrumental variables (IVs). Although genome-wide significant variants are typically preferred, the inclusion of variants with weaker association p-values is considered, as they may potentially improve power through an increased instrument number of instruments, while they may introduce weak instrument bias and attenuate effect estimates towards the null. Our simulation results show that even modest levels of pleiotropy substantially increase the variability of causal effect estimates, while the inclusion of weak IVs does not substantially affect the direction and variability of causal effect estimates in most cases. In real data analyses, we used two released versions of FinnGen GWAS summary statistics with different sample sizes as exposure GWASs to assess the influence of weak IVs. Here, the inclusion of IVs with higher exposure-association p-values resulted in weakened estimated effect sizes, particularly when the exposure GWAS sample size was small. These findings suggest that incorporating weak IVs is reasonable when the exposure GWAS sample size is large, but it poses a risk of falsely concluding null associations when the exposure GWAS sample size is small.

22.
arXiv (CS.AI) 2026-06-16

Agent Economics: An Entropy-Controlled Pluralistic Alignment Framework for Preventing Artificial Hivemind in Autonomous Agents

arXiv:2606.09039v2 Announce Type: replace Abstract: This study proposes the Behavioral Protocol Framework (BPF), an entropy-controlled pluralistic alignment framework designed to address two critical challenges in autonomous agent economies: the hivemind effect arising from excessive strategic convergence among agents and the lack of transparency in autonomous decision-making processes. The proposed BPF consists of three core modules: Mentalizing-based Social Intelligence (MbSI) grounded in Theory of Mind (ToM), Pluralistic Alignment (PA), and a Verifiable Execution Kernel (VEK). These modules are organically integrated within a closed-loop architecture that governs the entire lifecycle of agent behavior, from decision-making and execution to verification and feedback. To evaluate the proposed framework, a simulation environment implemented in Python and a Streamlit-based user interface will be developed. Through empirical experimentation, the study aims to examine whether the entropy-control mechanism of the PA module can effectively preserve strategic diversity among agents and mitigate collective convergence, while the VEK module provides a comprehensive and transparent audit trail of the decision-making process. The anticipated results are expected to demonstrate that the proposed framework can simultaneously enhance the stability, efficiency, and trustworthiness of autonomous agent economies. Consequently, this research offers a practical approach for developing robust, transparent, and accountable agent-native economic systems.

23.
medRxiv (Medicine) 2026-06-23

Systemic and Mucosal Antibody Correlates of Protection Against Bordetella pertussis in a Controlled Human Infection Model

Abstract Background Despite high vaccination coverage, pertussis has resurged globally. Whole-cell (wP) and acellular (aP) pertussis vaccines induce distinct immune profiles, yet immune correlates of protection against infection and symptomatic disease remain incompletely defined. We leveraged a controlled human infection model (CHIM) to identify systemic and mucosal humoral signatures associated with resistance to Bordetella pertussis. Methods Adults with documented history of vaccination had previously been enrolled in a CHIM study and challenged intranasally with B. pertussis D420. For the present work, longitudinal serum and nasal wash samples were analyzed using systems serology to comprehensively profile antibody features. Multivariate modeling and network analyses were performed to define discriminatory immune features. Findings Baseline aP vaccine antigen-specific antibodies did not distinguish infection outcomes. In wP-primed individuals, protection from B. pertussis infection was associated with broad, high-magnitude, polyfunctional antibody responses targeting non-canonical antigens, including BrkA, TcfA, OmpP, OmlA, FauA, and Pal. Protective signatures associated with resistance to symptomatic disease in both vaccine groups were characterized by enhanced Fc-receptor-engaging antibody profiles with distinct antigenic patterns shaped by vaccine history. Importantly, while conventional aP vaccine antigens failed to reliably distinguish individuals susceptible to infection or symptom development, correlates generated by integrated serum and mucosal models based on select non-canonical antigens achieved near-perfect discrimination of infection and symptom outcomes, outperforming models restricted to aP-vaccine. antigens only. Interpretation Resistance to infection was largely restricted to wP-primed individuals and was associated with integrated systemic and mucosal antibody responses directed against antigens beyond those included in acellular vaccines. Protection from symptomatic disease in both vaccine groups was linked to distinct antibody response signatures, shaped by prior vaccination history. These findings indicate that immune mechanisms preventing infection differ from those limiting clinical disease and provide a framework for redesign of next-generation pertussis vaccines aimed at blocking infection and symptomatic disease.

24.
medRxiv (Medicine) 2026-06-23

Innate immunity associates with protection from pneumococcal colonisation, but colonisation does not confer capsule-independent protection

Nasopharyngeal colonisation with Streptococcus pneumoniae is a prerequisite for transmission and disease and represents an important immunising event. While colonisation induces serotype-specific immunity, the mechanisms underlying heterologous protection remain unclear. We developed a controlled human infection model using pneumococcal serotype 15B and investigated colonisation dynamics, immunogenicity, and cross-protection against subsequent heterologous challenge with serotype 6B. Fifty-four healthy adults were intranasally inoculated with 15B at escalating doses. Colonisation rates peaked at 31.4% with 8 x 10 CFU per naris, lower than those historically observed with 6B and 3 strains. Density was also lower than previously observed with other strains. In vitro assays demonstrated that 15B adhered more readily to epithelial cells than 6B, but was less efficiently internalised, potentially reducing attack rates and colonisation density. Colonisation with 15B induced capsular polysaccharide-specific serum IgG, but baseline humoral immune measures did not predict protection from acquisition. Prior colonisation with 15B did not reduce acquisition of 6B upon re-challenge. Analysis of nasal microbiopsy samples revealed distinct innate activation signatures. Resistance to colonisation was associated with elevated baseline MIP-1 and MIP-1{beta} responses upon in vitro stimulation, whereas carriage was associated with enhanced chemokine and IL-6 responses. Local innate immune activation, rather than circulating antibody responses alone, may therefore contribute to colonisation control. We demonstrate that experimental colonisation with 15B does not confer heterologous protection against 6B and highlight the importance of mucosal innate immune conditioning in serotype-independent defence. Strategies enhancing nasal innate immune recruitment and activation may be required for broader protection against pneumococcal colonisation.

25.
arXiv (CS.LG) 2026-06-15

Optimal Hidden-Target Learning for Online Inventory Optimization on General Convex Sets

arXiv:2606.14679v1 Announce Type: new Abstract: Online inventory optimization (OIO) is online convex optimization with physical memory: inventory carryover makes the feasible action set depend on the past. A natural principle, used in stochastic inventory learning and recently in OIO under a single linear capacity constraint, is to maintain a hidden target chosen by an online learner and implement its projection onto the currently feasible order-up-to set. We prove that this simple principle is optimal for OIO on arbitrary bounded convex capacity sets. With online gradient descent as the base learner, the method improves the best known regret guarantee for OIO on general convex sets from inverse to inverse-square-root dependence on the common-demand probability, and we prove a matching lower bound. The same principle gives the first polylogarithmic regret guarantee for strongly convex losses and the first dynamic regret guarantee adapting to Euclidean path variation on general convex capacity sets. The analysis introduces a norm alignment principle: the right state variable is the distance from the hidden target to the feasible set, measured in the same norm as the projection. Under norm alignment, this distance evolves pathwise as a scalar queue, with target movement as arrival and common demand as service. This reduction to one-dimensional queue control resolves the state dependence and extends the guarantees to general convex capacity sets, beyond the reach of prior productwise approaches. Experiments on synthetic and real-world inventory data corroborate the theory.