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

Structuring The Future: Diffusion LLM Speculative Decoding via Calibrated Draft Graphs

Diffusion LLMs (dLLMs) have recently emerged as a powerful alternative to autoregressive LLMs (AR-LLMs) with the potential to operate at significantly higher token-generation rates. To unlock this potential, we present Spiffy, a speculative decoding algorithm to accelerate dLLM inference while provably preserving the model's output distribution. This work addresses the unique challenges involved in applying ideas from speculative decoding of AR-LLMs to dLLMs. Spiffy performs auto-speculation to eliminate the overheads of an independent draft model, structuring draft states in the form of a novel directed draft graph to take advantage of the bidirectional, blockwise nature of dLLM generation. These draft graphs are calibrated offline to maximize acceptance rates and are dynamically pruned during inference for improved computational efficiency. We present a detailed formulation of Spiffy and demonstrate its ability to accelerate LLaDA, Dream, and SDAR models in combination with KV caching and threshold-based dynamic unmasking leading to up to $8.6\times$ reduction in model inferences and $6.3\times$ acceleration in token rate.

02.
bioRxiv (Bioinfo) 2026-06-14

Somatic variant detection in normal tissues from single-cell sequencing data

A crucial advantage of single-cell sequencing (SCS) is its ability to identify somatic variants in individual cells, enabling phylogenetic analysis of cellular populations within bulk tissues. While identifying somatic variants in tumor tissues via SCS has become a common practice, doing so in normal tissues remains challenging due to the rarity of somatic variants in normal cells. To evaluate the feasibility of somatic variant calling from widely available single-nucleus RNA-seq (snRNA-seq) and single-nucleus ATAC-seq (snATAC-seq) data, we profiled a Cell-line mix of six HapMap samples prepared by the SMaHT consortium using 10x Genomics 5' snRNA-seq (12k cells with 36k mean reads per cell) and snATAC-seq (11k cells with 14k median high-quality fragments per cell) for variant calling. PacBio long-read whole genome sequencing (WGS) data (109x) generated from individual cell lines were used as ground truth. Two computational tools, Monopogen and SComatic, were used for somatic variant calling from the SCS data. Monopogen achieved single nucleotide variant (SNV) detection accuracies of 93.30% in the snRNA-seq and 99.64% in the snATAC-seq data, both of which outperformed SComatic (74.35% and 94.29%, respectively). Monopogen also consistently detected somatic SNVs at cellular fractions as low as 0.5% (2.54% in snRNA and 0.81% in snATAC) in individual samples. Notably, snATAC-seq exhibited higher genomic coverage breadth and larger number of variants detected than snRNA-seq. While the SCS data have lower overall genome coverage than that of the bulk WGS, the single-cell level variant resolution allows Monopogen to assign variants to their cells of origin with over 80% accuracy in both RNA and ATAC modalities, thereby facilitating studies of clonal evolution and cell-type-specific mutagenesis. Other benchmarking methods were also evaluated (DeepVariant, Cellsnp-lite and Mutect2) for comparison. In conclusion, our study demonstrated the feasibility of performing reliable single-cell somatic mutation calling in a cell-line mixture and discussed the strengths and limitations of current computational methods when applied to normal tissues.

03.
arXiv (CS.AI) 2026-06-24

Topological Neural Dynamics: A Neuron-wise Framework for Sequence Modeling

arXiv:2606.21295v2 Announce Type: replace-cross Abstract: Existing sequence models, including RNNs, LSTMs, continuous-time networks, and Transformers, share a common structural principle: layer-wise dynamics, where all neurons in the same layer co-evolve through a shared parameterized operator, leaving individual neurons no freedom to evolve independently. Yet in many complex dynamical systems, rich global behavior emerges precisely from locally evolving units interacting through structured connectivity. Inspired by this principle, we introduce Topological Neural Dynamics (TND), a sequence modeling framework that shifts computation from layer-wise to neuron-wise dynamics. TND represents a neural system as a directed neuron graph, an interaction operator, and a local dynamics function, where each neuron evolves independently and collective computation emerges from interactions through the explicit graph topology. We instantiate TND as a discrete-time graph-coupled dynamical system and evaluate it as a case study on a behavior cloning task in single-player Pong. Compared with Vanilla RNN, Sparse RNN, LSTM, Closed-form continuous-time neural network (CfC), and Transformer baselines, TND achieves the best catch rate and a mean of 17.47 consecutive catches per round, more than three times that of the strongest baseline. These results suggest that shifting from layer-wise to neuron-wise dynamics provides an effective inductive bias for sequence modeling.

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

Judging to Improve: A De-biased VLM-as-3D-Judge Protocol for Single-Image 3D Generation

arXiv:2606.20364v1 Announce Type: new Abstract: A companion study established a de-biased, cross-model VLM-as-3D-judge that reliably ranks single-image-to-3D mesh quality where cheap geometry and CLIP proxies fall short. This paper asks: can that judge's preferences specialize a strong open generator, TRELLIS, on one asset class (furniture), cheaply and without human labels? Taking the judge from ranking to optimization is where the work lives. Pushing a VLM judge into the training and evaluation loop exposes failure modes ranking never triggered, so our contribution is an optimization-grade hardening of the judge: a training judge (Qwen2.5-VL-7B) held distinct from an evaluation judge (InternVL3-8B) to break circularity; position-bias correction; and fixes for three failure modes (image overload, geometry-hiding splat renders, and reference-free judging that rewards clean-but-wrong outputs), with calibration evidence (clear-gap win-rate 0.83-1.0; base-vs-base ~0.5). Using this protocol as an independent evaluator, and working only from public models and data with lightweight parameter-efficient adaptation, we find our methods match the strong base rather than exceed it. Independent base samples carry essentially no learnable preference (0.94 order-flip rate), so signal must be engineered by quality-contrastive construction. Across six adaptation methods, two input regimes, and a severity sweep, the most targeted - conditioner repair under severe degradation - reaches parity (0.50) with the base, while no method clears the >=65% win-rate target. The result is mechanistic: clean inputs saturate the judge, flow-DIT fine-tuning washes out through the sampler, and conditioning repair is the locus that moves geometry. Win-rates are directional at n=8 objects. Matching a strong public-data base with cheap adaptation is itself informative: exceeding it needs more than lightweight PEFT on public data, and the judge protocol is reusable.

05.
arXiv (CS.AI) 2026-06-15

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

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

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

LapidaryEngine: Fully Conversational Crystal Generation

arXiv:2606.14215v1 Announce Type: new Abstract: The emergence of Large Language Models (LLMs) has inspired the vision of generating bespoke crystal materials directly from natural-language instructions, enabling users to design materials through intuitive, conversational interaction. Existing text-to-crystal generative models represent important early steps toward this goal, but they suffer from two critical limitations: (i) restricted input formats that require highly structured descriptions (e.g., chemical formulas), and (ii) one-directional generation, where models can map text to crystal but cannot perform the inverse. These limitations prevent fully conversational workflows and hinder alignment with users' inherently ambiguous and evolving desiderata. We address these challenges with LapidaryEngine, the first model to support fully conversational crystal generation. LapidaryEngine accepts free-form natural-language requests and performs iterative refinement and editing in a dialogue-like manner. The key innovation is a pivot representation, a third, intermediate form that enables bidirectional translation between text and crystal structures despite the absence of direct paired datasets. Leveraging this pivot allows robust interpretation of user feedback and precise structural control. We demonstrate LapidaryEngine across diverse tasks, including insulator discovery, stability optimization, compositional modification, and structural editing, showcasing its ability to align generated materials with user intent in an interactive manner.

07.
arXiv (math.PR) 2026-06-16

Sharp freezing time estimates for the subcritical Facilitated Exclusion Process

arXiv:2606.15233v1 Announce Type: new Abstract: We investigate the exact transience time of the Facilitated Exclusion Process (FEP) on the one-dimensional torus with $N$ sites. The FEP exhibits an active/inactive phase transition at critical density $1/2$, such that in the subcritical density regime $(0,1/2)$, it becomes frozen after a finite time period – the transience time or freezing time. We first show that for the FEP starting from a Bernoulli product measure of marginal density $\rho \in (0,1/2)$, the transience time has exactly the scale of $\Theta(\log^3 N)$. Secondly, we prove that in the near-critical case $\rho \simeq 1/2 - N^{-\alpha}$ for $\alpha \in (0,1)$, the transience time is polynomial and has a scale of $N^{1 \wedge (2\alpha)}$. The key idea is to estimate the typical size of locally supercritical intervals of the initial distribution, which has order $\log N$ in the subcritical case and $N^{1 \wedge (2\alpha)}$ in the near-critical case. In the subcritical case this is enough, whereas in the near-critical case we need additional dynamical decorrelation inequalities to apply this static result to estimate the freezing time.

08.
arXiv (quant-ph) 2026-06-16

Analytical solution of the Schr\"{o}dinger equation with $1/r^3$ and attractive $1/r^2$ potentials: Universal three-body parameter of mixed-dimensional Efimov states

arXiv:2601.19517v2 Announce Type: replace-cross Abstract: We study the Schr\"{o}dinger equation with $1/r^3$ and attractive $1/r^2$ potentials. Using the quantum defect theory, we obtain analytical solutions for both repulsive and attractive $1/r^3$ interactions. The obtained discrete-scale-invariant energies and wave functions, validated by excellent agreement with numerical results, provide a natural framework for describing the universality of Efimov states in mixed dimension. Specifically, we consider a three-body system consisting of two heavy particles with large dipole moments confined to a quasi-one-dimensional geometry and resonantly interacting with an unconfined light particle. With the Born-Oppenheimer approximation, this system is effectively reduced to the Schr\"{o}dinger equation with $1/r^3$ and $1/r^2$ potentials, and manifests the Efimov effect. Our analytical solution suggests that, for repulsive dipole interactions, the three-body parameter of the mixed-dimensional Efimov states is universally set by the dipolar length scale, whereas for attractive interactions it explicitly depends on the short-range phase. We also investigate the effects of finite transverse confinement and find that our analytical results are useful for describing the Efimov states composed of two polar molecules and a light atom.

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

Automated 3D Kinematic Monitoring for Circadian Activity and Anomaly Detection in Juvenile Fish

Precision aquaculture faces a "phenotyping bottleneck" in tracking high-resolution behavioral traits, as conventional methods cannot quantify instantaneous three-dimensional (3D) physical exertion. To address this, we present a high-throughput 3D behavioral phenotyping framework integrating deep learning object detection with binocular stereo vision for real-time monitoring of juvenile tilapia in high-density environments. The system automates non-contact body length estimation and reconstructs 3D swimming trajectories from absolute spatial coordinates. By eliminating 2D perspective distortions, this approach precisely quantifies 3D velocity and acceleration, marking the first estimation of true physical swimming speeds in free-roaming juveniles. Results show the framework successfully establishes circadian locomotor baselines, serving as an early warning system for physiological stress and providing an objective metric for fish vitality.

10.
arXiv (CS.AI) 2026-06-12

Modern analog computing for solving differential and matrix equations

arXiv:2606.13179v1 Announce Type: cross Abstract: In recent years, driven by the computational demands of data-intensive applications such as artificial intelligence and scientific computing, analog computing has gained renewed interest. Given the diversity of computational tasks and recent advancements in analog CMOS circuits and resistive memory technologies, we refer to the evolving landscape as modern analog computing. In this context, we identify three core computational primitives: solving differential equations, solving matrix equations, and performing matrix-vector multiplications, and we explore the connections among them. We also examine various hardware implementations of these analog computing operators, including those built with discrete components, integrated circuits, and resistive memory devices. Among these, resistive memory arrays emerge as particularly promising due to their implementation efficiency. The paper then surveys recent progress in leveraging modern analog computing to solve differential and matrix equations using both advanced analog CMOS circuits and resistive memory arrays. Finally, we discuss the applications of these circuits, the precision and scalability issues and their potential solutions, the relationship with in-memory computing, and the unique computational complexity of analog computing. This paper provides a unified perspective on analog computing, highlighting its strengths, current developments, and challenges, and positioning it as a pivotal enabler of next-generation computational frontiers.

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

How Inference Compute Shapes Frontier LLM Evaluation

arXiv:2606.17930v1 Announce Type: new Abstract: AI evaluations are shifting toward harder tasks that benefit from longer trajectories involving tool use and iterative problem solving. As a result, performance is increasingly sensitive to the amount and allocation of compute available at test time ("inference compute"). Yet many evaluations still report performance at a single restrictive budget, meaning that low scores may reflect the evaluation setup rather than the model's underlying capability. To test this, we evaluate up to 12 frontier language models on seven challenging benchmarks spanning software engineering, mathematics, medicine, and cybersecurity. We use a controlled setup combining three simple inference-scaling interventions: larger token budgets, context compaction, and repeated submission attempts, guided either by the model itself or by minimal correctness feedback. We find three main results. First, larger token budgets substantially improve performance on benchmarks across multiple domains, including cybersecurity, FrontierMath, Humanity's Last Exam, and TerminalBench. Second, fixed-budget evaluations can increasingly understate frontier capability as models advance. Newer models reach higher performance at large budgets, where they unlock harder tasks and solve them more reliably. Third, benchmarks differ in which inference-scaling methods help most: repeated submission broadly improves performance, but the value of larger token budgets, external feedback, and parallel attempts varies by benchmark. Overall, our results show that benchmark scores are protocol-dependent. We therefore argue that evaluations should report capability as a function of inference-time compute, specify protocol choices explicitly, and compare model generations over a large shared compute range at matched budgets, especially in safety- or policy-relevant settings.

12.
arXiv (CS.AI) 2026-06-19

Structuring and Tokenizing Distributed User Interest Context for Generative Recommendation

arXiv:2606.20554v1 Announce Type: cross Abstract: Generative recommendation is an emerging paradigm that has shown promise in industrial recommendation systems, aiming to predict users' next interactions from their historical behaviors. At the core of generative recommendation lies item tokenization, which bridges item semantics and recommendation models. However, existing methods often struggle to effectively organize and inject complex user-behavioral and item-semantic contexts into recommendation models simultaneously. On the one hand, existing graph-based integration methods, such as graph serialization and graph neural networks, either suffer from scalability issues or exploit only local graph information. On the other hand, existing semantic tokenization methods typically rely on heuristics and lack explicit supervision signals, which may lead to inaccurate or suboptimal semantic representations. To address these limitations in user interest context modeling, we propose G2Rec, a scalable framework that unifies holistic graph-based user co-engagement modeling with semantic tokenization for industrial-scale generative recommendation. Overall, G2Rec enables recommendation models to capture holistic and semantically grounded user interest prototypes without requiring ground-truth user interests, thereby providing more comprehensive and accurate modeling of user behavior contexts in industrial sequential recommendation. Online deployment across product surfaces and extensive experiments on public datasets demonstrate the superiority of G2Rec over existing methods.

13.
Nature (Science) 2026-06-10

A vast whale necropolis has been found

In the Indian Ocean, a deep-sea area roughly 1,200 kilometres long and 7 kilometres deep was found to harbour an ecological landmark site of whale remains. In the Indian Ocean, a deep-sea area roughly 1,200 kilometres long and 7 kilometres deep was found to harbour an ecological landmark site of whale remains.

14.
arXiv (CS.CL) 2026-06-24

Beyond Logprobs: A Multi-Signal Confidence Engine for LLM-Based Document Field Extraction

Authors:

In high-stakes document processing pipelines, including financial reconciliation, compliance verification, and procurement automation, an LLM extraction that is silently wrong is more dangerous than one that is visibly absent. The central challenge is not extraction accuracy alone but reliable confidence estimation: knowing, field by field, whether an extraction can be trusted for automation or deferred to human review. Token-level log-probabilities, verbalized confidence, and multi-sample self-consistency all collapse toward all-positive behaviour at practical thresholds, offering no reliable separation between trustworthy and untrustworthy extractions. We present ExtractConf, a cross-domain, field-agnostic confidence engine that grounds confidence estimation in two structurally different readings of the same document. A field-guided Hunter call extracts each field under schema-slot completion pressure; a document-guided Mapper call scans holistically and surfaces values grounded in document content. This asymmetry yields different failure modes: Hunter hallucinates values for absent fields, while Mapper misses visually non-salient ones. Their disagreement is independently informative. ExtractConf fuses cross-call disagreement, LLM-internal uncertainty, OCR, image quality, and spatial layout into a classifier requiring no domain-specific rules or retraining. On DocILE (55-field invoices, 26% failure rate), it achieves 0.928 ROC AUC and reduces selective prediction risk by 70% over logprob-mean. At 80% coverage, accuracy reaches 99.1%, enabling a practical human-in-the-loop workflow. Zero-shot transfer to CORD receipts achieves 0.858 AUC; lightweight Lasso recalibration reduces ECE by 89% and Brier by 43%, confirming the signals generalise across document domains.

15.
arXiv (CS.AI) 2026-06-11

A Survey on Evaluating Quality and Trustworthiness in LLM-Generated Data

arXiv:2601.17717v3 Announce Type: replace Abstract: Large Language Models (LLMs) have emerged as powerful tools for generating data across various modalities. By transforming data from a scarce resource into a controllable asset, LLMs mitigate the bottlenecks imposed by the acquisition costs of real-world data for model training, evaluation, and system iteration. However, ensuring the high quality of LLM-generated synthetic data remains a critical challenge. Existing research primarily focuses on generation methodologies, with limited direct attention to the quality of the resulting data. Furthermore, most studies are restricted to single modalities, lacking a unified perspective across different data types. To bridge this gap, we propose the LLM Data Auditor framework. In this framework, we first describe how LLMs are utilized to generate data across six distinct modalities. More importantly, we systematically categorize intrinsic metrics for evaluating synthetic data from two dimensions: quality and trustworthiness. This approach shifts the focus from extrinsic evaluation, which relies on downstream task performance, to the inherent properties of the data itself. Using this evaluation system, we analyze the experimental evaluations of representative generation methods for each modality and identify substantial deficiencies in current evaluation practices. Based on these findings, we offer concrete recommendations for the community to improve the evaluation of data generation. Finally, the framework outlines methodologies for the practical application of synthetic data across different modalities.

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

DoubtProbe: Black-Box Jailbreak Defense via Structural Verification and Semantic Auditing

As large language models (LLMs) are increasingly deployed in user-facing systems, black-box jailbreak defense has become an important practical problem. Existing defenses often rely on known-attack coverage, prompt-level semantic judgment, or local runtime control, yet these paths can become unstable under evolving prompt packaging, expression rewriting, and structure manipulation. We observe that many black-box jailbreaks do not remove the harmful goal, but reorganize the information needed to express and execute it, thereby evading safety alignment while remaining recoverable during generation. Motivated by this observation, we propose DoubtProbe, a dual-branch inference-time defense framework that combines structural verification with semantic auditing and formulates black-box jailbreak defense as consistency checking under controlled transformation. The structural branch extracts a structured representation from the original request, reconstructs the request under representation constraints, and detects information-preservation failures between the original and reconstructed requests; the semantic branch audits the original prompt directly. We evaluate DoubtProbe against representative black-box defenses on jailbreak and benign-request benchmarks, and further test backbone transfer from Qwen2.5-72B to Llama-3.1-70B. Results show that DoubtProbe achieves a stronger and more stable defense-utility trade-off: on Qwen2.5-72B, it reduces the JBB attack success rate from 0.293 to 0.100 and the CodeAttack attack success rate from 0.152 to 0.001, while maintaining false positive rates of 0.022 and 0.016 on AlpacaEval and OR-Bench; the same pattern remains stable on Llama-3.1-70B. These findings show that structural inconsistency signals provide a practical and generalizable basis for black-box jailbreak defense, especially when combined with semantic auditing.

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

Attention mechanisms and transfer learning for robust peach leaf damage classification under domain shift

Artificial intelligence provides a practical framework for crop damage assessment from imagery data, supporting early decision-making in agricultural management. In peach orchards, climate change increases abiotic stress and biotic pressures, including pests and diseases, which often produce visually similar foliar symptoms. This overlap makes manual diagnosis difficult, especially across multiple fields with varying environmental conditions, highlighting the need for automated models with strong generalization ability. We propose an image-based classification approach for peach leaf damage detection. A benchmark dataset was created through manual annotation of publicly available images, consisting of 1,366 peach leaves across six damage categories. Several deep learning architectures were evaluated. EfficientNet models achieved the best results, with EfficientNetB0 reaching 92.9 percent accuracy, EfficientNetB3 achieving 91.5 percent, and EfficientNetB5 showing the strongest performance on minority classes. DenseNet121 reached 92.6 percent accuracy. The integration of the Convolutional Block Attention Module (CBAM) improved performance in several backbones, particularly EfficientNetB5 and InceptionV3, while showing limited or negative impact in others. The CBAM-enhanced EfficientNetB5 achieved the best overall accuracy of 93.3 percent. To evaluate robustness under realistic conditions, a local dataset of 180 images across four classes was collected, and transfer learning strategies were applied to address domain shift. Three fine-tuning strategies were tested. EfficientNetB3 combined with CBAM achieved the best performance in the local domain, reaching a 93 percent macro F1-score after transfer. Overall, attention-based models showed improved robustness for minority classes and better generalization across different field conditions.

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

Quantification of Uncertainty with Adversarial Models in Medical Image Segmentation

Reliable pixel-level uncertainty quantification holds the potential to transform clinical workflows by enabling high-fidelity longitudinal monitoring and distinguishing true pathological changes from artifacts. Ideally, these models provide the stability required for critical treatment planning and surgical intervention. However, standard deep learning models often suffer from miscalibration, yielding overconfident predictions that mask underlying vulnerabilities at subtle pathological boundaries. To address this, we propose QUAM-SM, a post-hoc framework using targeted adversarial search to identify "adversarially fragile" pixels. By actively seeking perturbations that expose predictive instability, our method highlights regions where decisions are most vulnerable to being flipped. Importantly, the framework disentangles epistemic uncertainty from aleatoric uncertainty. Experiments on two public datasets with multiple expert annotations demonstrate that QUAM-SM outperforms both standard and recent uncertainty estimation approaches in terms of reliability and boundary sensitivity. Code is available at https://github.com/HanaJebril/quam_sm

19.
arXiv (CS.LG) 2026-06-24

AsyncOPD: How Stale Can On-Policy Distillation Be?

arXiv:2606.24143v1 Announce Type: new Abstract: On-policy distillation (OPD) trains a student on its own rollouts guided by teacher feedback and is becoming increasingly important for large language model (LLM) post-training. Like reinforcement learning (RL), however, OPD faces an on-policy systems bottleneck, as rollouts can dominate training time for reasoning workloads. Asynchronous training pipelines can alleviate this bottleneck by decoupling rollout generation from learner updates, but doing so introduces stale-policy data. While prior work has studied stale data in asynchronous RL, its effects in OPD remain underexplored. We present the first systematic study of staleness in asynchronous OPD, focusing on a practical setting where teacher feedback is implemented through local KL losses and full-vocabulary teacher logits are too expensive to store or transfer, necessitating finite teacher-score caches. We first show that KL direction changes the stale-data problem: teacher-weighted forward KL is more robust to stale rollouts, whereas student-weighted reverse KL is vulnerable. Second, for this vulnerable reverse-KL case, we study whether methods designed to stabilize asynchronous RL can mitigate OPD staleness. In our experiments, they do not improve over a simpler OPD-specific surrogate: recomputing the reverse-KL signal under the current student at learner time. Third, we analyze how finite teacher-score caches create a bias-variance tradeoff for sparse and sampled reverse-KL OPD estimators. This motivates multi-sample Monte Carlo (MC), which preserves MC correctability while reducing one-sample variance. Finally, we present and open-source AsyncOPD, a fully asynchronous OPD training pipeline built from these estimator choices. Experiments show that AsyncOPD improves training throughput by $1.6\times$ to $3.8\times$ over strict synchronous training while reaching comparable accuracy.

20.
bioRxiv (Bioinfo) 2026-06-21

Expanding the GUSome: Structure-guided identification and characterization of gut microbial β-glucuronidases

The gut microbiome-encoded {beta}-glucuronidase (GUS) enzymes have a significant effect on human physiology through their deglucuronidation activity on endogenous and exogenous glucuronides. GUS activity also significantly influences the pharmacokinetics, efficacy and toxicity of various drugs including chemotherapeutic drugs. Given their crucial role in drug metabolism, GUS enzymes have emerged as promising targets for therapeutic intervention. Here, we have identified and characterized 79 unique GUS enzymes through a structure-guided approach. Structural modelling of these GUS enzymes revealed a conserved core and active-site residues with significant variations in the number and nature of the C-terminal domains. A new classification system based on the number and type of additional C-terminal domains is presented for the GUS proteins. Further, GUS enzymes have been categorized into different loop categories linked to their substrate preferences. The relationship between domain architecture and loop-type is explored by sequence similarity network analysis. We could successfully express, purify and validate GUS processing capability of a panel of identified GUS proteins. The nature of oligomer organization has been deciphered by SEC and DLS studies. Further, we have identified additional GUS enzymes capable of processing SN-38G, glucuronidated form of anticancer drug, irinotecan. These newly identified GUS enzymes will offer valuable insights into gut microbial GUS diversity and their role in understanding the population-specific drug-induced adverse effects on human health.

21.
arXiv (quant-ph) 2026-06-15

Quantum geometrical description of hole spin qubits far away from the $\Gamma$-point

arXiv:2606.14683v1 Announce Type: cross Abstract: Hole spin qubits provide one of the leading platforms for spin-based quantum computing due to their large intrinsic spin-orbit interaction (SOI), which enables fast electrical manipulation. The SOI of planar quantum dots has mostly been investigated in theoretical studies by examining the SOI already present in the two-dimensional hole gas (2DHG). Here, we study the SOI created by the in-plane confinement by deriving non-perturbative effective Hamiltonians numerically for hole spin qubits. We find that the quantum geometry of the 2DHG naturally emerges, leading to a meaningful non-perturbative definition of pseudospin valid far away from the $\Gamma$-point. The SOI of the 2DHG and of the in-plane confinement have different forms; therefore, they cannot be turned off simultaneously, ruining the perfect spin-orbit switch functionality of spin qubits. We construct effective Hamiltonians using the symmetry approach for various low-dimensional hole systems: (i) a heavy-hole confined in a SiGe/Ge/SiGe heterostructure, (ii) a light-hole confined in SnGe/Ge, (iii) a gate-defined nanowire in SiGe/Ge/SiGe, and (iv) a hole confined in a Ge/Si core/shell nanowire. The non-perturbative effective Hamiltonians provide results with excellent agreement with the full Hamiltonians.

22.
arXiv (quant-ph) 2026-06-11

Magneto-Optical Trapping of a Metal Hydride Molecule

arXiv:2512.22350v2 Announce Type: replace-cross Abstract: We demonstrate a three-dimensional magneto-optical trap (MOT) of a metal hydride molecule, CaH. We are able to scatter $\sim$$10^{4}$ photons with vibrational loss covered up to vibrational quantum number $\nu=2$. This allows us to laser slow the molecular beam near zero velocity with a "white-light" technique and subsequently load it into a radio-frequency MOT. The MOT contains $230(40)$ molecules, limited by beam source characteristics and predissociative loss of CaH. The temperature of the MOT is below one millikelvin. The predissociative loss mechanism could, in turn, facilitate controlled dissociation of the molecule, offering a possible route to optical trapping of hydrogen atoms for precision spectroscopy.

23.
medRxiv (Medicine) 2026-06-23

Shared Polygenic Architecture Across Arteriopathies: An Integrative Cross-Trait Analysis

Background: Non-monogenic arteriopathies are often classified as distinct entities according to the arterial territory involved, yet they share clinical features and may co-occur in the same individual. This pattern suggests shared susceptibility across anatomically distinct arteriopathies, potentially driven by common biological and genetic mechanisms. Methods: We investigated the shared genetic architecture of five arteriopathies (cervical artery dissection (CeAD), intracranial aneurysm (IA), spontaneous coronary artery dissection (SCAD), aortic aneurysm and dissection (AAD), and fibromuscular dysplasia (FMD)) using LD score regression, Association analysis based on SubSETs (ASSET), pairwise Multi-Trait Analysis of Genome-wide association summary statistics (MTAG), pleiotropy mapping and Mendelian randomization (MR) to identify shared loci and prioritise candidate causal genes. Results: LD score regression identified significant positive genetic correlations between CeAD-SCAD (rg = 0.64), IA-AAD (rg = 0.33), IA-SCAD (rg = 0.37), CeAD-AAD (rg = 0.56) and SCAD-AAD (rg = 0.20). ASSET identified 37 shared independent loci, and in MTAG analyses, one novel locus was identified for CeAD and SCAD (SLC39A8) and one for IA (FGF5). 13 loci showed strong cross-trait colocalization, including PHACTR1, LRP1, and CDKN2B-AS1. Using the Genotype-Phenotype Map, we found that arteriopathy-associated variants colocalized with blood pressure- and migraine-related traits, while many showed effect directions opposite to those observed for coronary artery disease. Proteome-wide MR identified 67 circulating proteins associated with at least one trait, including ECM1 and SHISA5 for CeAD and FGF5 for IA, with 17 supported by colocalization. Transcriptome-wide MR identified 204 colocalized tissue?specific signals, of which, 14 were shared across multiple traits. Enrichment analyses implicated pathways related to vascular development, smooth muscle cell function, extracellular matrix organization, and TGF-? signaling. Conclusions: These findings support shared genetic architecture across anatomically distinct arteriopathies, implicating pathways involved in vascular structure and prioritising therapeutic targets for future mechanistic investigation.

24.
PLOS Computational Biology 2026-06-09

Evolution of phenocopying in a dynamical model of developmental trajectories

by Yuuki Matsushita, Archishman Raju Developmental trajectories are known to be canalized, or robust to both environmental and genetic perturbations. However, even when these trajectories are decanalized by an environmental perturbation outside the range of conditions to which they are robust, they often produce phenotypes similar to known mutants, called phenocopies. This correspondence between the effects of environmental and genetic perturbations has received little theoretical attention. Here, we study an abstract regulatory model that is evolved to follow a specific trajectory. We then study the effects of small and large perturbations to the trajectory, both by changing parameters and by perturbing the state at specific times. We find that the phenomenon of phenocopying emerges in evolved trajectories and is not present in a null model of randomly sampled trajectories. Our results suggest that, in this class of dynamic models, evolution can allow high-dimensional phenotypic landscapes to simultaneously exhibit robustness and phenocopying.

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medRxiv (Medicine) 2026-06-11

Long-term Penetrance of Disease Variants in Genes Prioritized for Genomic Newborn Screening: Evidence from Adult Biobanks

Importance: Genomic newborn screening (gNBS) is a potential public health intervention, but its positive predictive value (PPV) remains uncertain. Estimating the prevalence and penetrance of pathogenic and likely pathogenic (P/LP) variants in genes prioritized for screening may clarify the long-term PPV and clinical utility of gNBS. Objective: To compare ICD-based ascertainment, electronic medical record (EMR) review, and clinical assessment of genetic disorders in adults with P/LP variants in 54 genes prioritized for gNBS. Design: Two-cohort observational study with EMR review and clinical assessment in the hospital-based cohort. Setting: The U.K. Biobank (UKB) and Mass General Brigham Biobank (MGBB). Participants: 451,877 adults from the UKB and 53,371 from the MGBB, all with exome sequencing data. Exposures: P/LP variants in 54 genes prioritized through expert consensus for gNBS, in genotypes consistent with each gene's inheritance pattern. Main outcomes and measures: The primary outcome was the absolute difference in the proportion of MGBB participants identified as affected by ICD versus EMR ascertainment. Secondary outcomes included findings from clinical assessments of undiagnosed MGBB participants, corrected UKB penetrance estimates, and extrapolation to U.S.. annual birth cohorts and living adults. Results: P/LP variants were identified in 665 UKB participants (0.15%) and 82 MGBB participants (0.15%), approximately 1 in 650. In MGBB, EMR review revealed that 58/82 individuals (70.7%) were undiagnosed, although 25 of 58 (43.1%) had documented symptoms. Disease-associated ICD codes were found in 39.0% (32/82) of participants, whereas EMR review identified symptoms in 59.8% (49/82, McNemar P