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01.
arXiv (math.PR) 2026-06-18

Second-Order Approximation of Limit Order Books in a Single-Scale Regime

arXiv:2308.00805v3 Announce Type: replace-cross Abstract: We establish a first- and second-order approximation for an infinite dimensional limit order book model in a single (critical) scaling regime where market and limit orders arrive at a common time scale. With our choice of scaling we obtain non-degenerate first- and second-order approximations for the price and volume dynamics. While the first-order approximation is given by a coupled ODE-PDE system, the second-order approximation is described in terms of an infinite-dimensional stochastic evolution equation driven by a cylindrical Brownian motion. The driving noise processes exhibit a non-trivial correlation in terms of the model parameters. We prove that the evolution equation has a unique solution and that the sequence of standardized limit order book models converges weakly to the solution of the evolution equation. The proof uses a non-standard martingale problem. We calibrate a linearized model to market data and explain how our model can be used for deriving confidence intervals of portfolio liquidation values.

02.
arXiv (CS.LG) 2026-06-11

Triangular-Reference Schrödinger Bridges for Time Series Generation

arXiv:2605.27478v3 Announce Type: replace-cross Abstract: Schrödinger bridges for time series (SBTS) generate synthetic paths by projecting, in relative entropy, a Brownian reference onto the path laws that match the joint distribution of the data on the observation grid. The Brownian reference, however, fixes the quadratic variation of the generated paths, which is restrictive when stochastic volatility, correlated noise, or rank-deficient covariance structures must be reproduced. We introduce "Triangular-Reference Schrödinger Bridges for Time Series" (TR-SBTS), which keeps the entropy-projection backbone of SBTS but replaces the Brownian reference by a triangular, volatility-informed, intervalwise frozen reference on a state augmented with latent covariance descriptors. The construction remains a single entropy projection on the augmented state: the minimiser is the \(h\)-transform of the reference, and on each frozen interval the optimal drift has the logarithmic-gradient form \(b^\star(t,x)=A\,\nabla\log H(t,x)\), intrinsic to the active covariance directions when the frozen covariance \(A\) is degenerate. We prove stability of the frozen approximation and consistency of the associated regularised kernel estimators, describe a reference-aware Nadaraya–Watson implementation of the conditional next-increment law, and evaluate the construction on numerical experiments.

03.
arXiv (quant-ph) 2026-06-17

Stochastic signal sensing with finite energy and dead time at the fundamental quantum limit

arXiv:2606.18133v1 Announce Type: new Abstract: State preparation, measurement, and reset operations take finite time and use finite energy in realistic experiments, yet the impact of this on optimal quantum metrological protocols is not properly understood. We study the effect on sensing a stochastic signal, relevant for the detection of ultralight dark matter and other searches for fundamental physics. We prove that two-mode squeezed vacuum is the optimal probe state given a finite mean-energy constraint for a family of incoherent sensing problems, including noise sensing and quantum illumination. For estimating a gain independent of a loss, we show that entanglement is a required resource to achieve the fundamental quantum limit and observe a non-Gaussian to Gaussian transition in the optimal unentangled state as the dead time increases. We apply our results to bulk acoustic wave resonators.

04.
arXiv (CS.AI) 2026-06-12

Variational Learning for Insertion-based Generation

arXiv:2606.02133v3 Announce Type: replace-cross Abstract: Non-monotonic sequence generation methods, such as masked diffusion models, provide a flexible alternative to left-to-right autoregressive modeling by allowing tokens to be generated in non-fixed and prescribed orders. Despite their practical advantages, most existing non-monotonic models are order-agnostic and rely on a fixed-length grid, limiting their ability to support variable-length generation and adaptive insertion order. In this work, we introduce a probabilistic framework for learning insertion order in variable-length insertion models. We formalize a bijective correspondence between insertion trajectories and permutations, which enables an exact reparameterization of the data likelihood as a sum over permutations. Building on this result, we propose the Insertion Process (IP), a stochastic generative model that jointly learns where to insert, what to insert, and when to terminate, trained via permutation-based variational inference. Unlike prior fixed-canvas approaches, IP natively supports variable-length generation and learns data-driven preferences over insertion orders. Experiments on goal-conditioned planning and molecular string generation demonstrate that learning insertion order improves both modeling quality and generalization in domains without a canonical left-to-right structure.

05.
medRxiv (Medicine) 2026-06-22

Sex-specific multimorbidity clusters and all-cause mortality in relatively healthy older adults: findings from the ASPREE cohort

Background: Multimorbidity is common in older adults, but sex differences in chronic condition clustering remain unclear. This study explored multimorbidity clusters and their associations with all-cause mortality among community-dwelling adults aged 70 years and over. Methods: This was a secondary analysis of data from 16,095 Australian ASPREE participants aged at least 70 years without prior dementia or cardiovascular disease. Fifteen baseline chronic conditions were grouped using latent class analysis (LCA). Observed-to-expected (O/E) ratios characterised conditions over-represented within clusters, and Cox proportional hazards models assessed associations with all-cause mortality. Results: Among 16,095 participants (mean age 74 years), 88.3% had multimorbidity at baseline; 4,217 deaths occurred over a median follow-up of 10.85 years. Five clusters were identified overall: hypertension and dyslipidemia (52.1%), gout and metabolic (14.4%), depressive symptoms, osteoporosis and frailty (10.0%), anaemia and kidney disease (10.2%), and hypotension, thyroid disorder and past cancer (13.3%). Sex-stratified analyses revealed three clusters in males and four in females. The frailty, depressive symptoms and osteoporosis cluster was associated with higher mortality in both sexes (aHR 1.56 [95% CI 1.40-1.73] in males; 1.68 [1.49-1.89] in females). Higher mortality was also observed for the metabolic, gout and kidney disease cluster in males (aHR 1.63 [1.47-1.81]) and the gout, anaemia and kidney disease cluster in females (aHR 1.96 [1.74-2.21]). Conclusions: Distinct multimorbidity clusters differed by sex and were associated with increased all-cause mortality. These findings may support risk stratification, targeted screening, and more person-centred management of older adults with multimorbidity.

06.
arXiv (CS.CV) 2026-06-24

Face versus Body Tracking for Human-Robot Interaction: An Egocentric Dataset

Meaningful human-robot interaction (HRI) requires a robot to continuously assess user engagement through persistent user tracking. However, state-of-the-art Multi-Object Tracking models are heavily optimized for surveillance or autonomous driving. A social robot faces distinct egocentric challenges, such as humans moving in unpredictable nonlinear patterns, obstructing each other, or leaving and reentering the scene. These dynamics trigger frequent identity switches (IDSW), causing the robot to lose its footing mid-conversation. To address this, we introduce a focused, custom-annotated egocentric dataset collected via the Furhat robot. We present a systematic evaluation isolating detection errors from tracking logic, comparing face versus body tracking, and assessing the impact of extended memory and appearance re-identification (ReID). Results indicate that increasing temporal memory mitigates prolonged occlusions but fails on complex dynamic events. Integrating ReID resolves complex switches but exhibits opposing effects: it substantially improves body tracking stability, yet causes facial IDSW to spike due to profile angle sensitivity. Ultimately, our optimized pipeline reduces IDSW by 49% compared to a standard tracking-by-detection baseline, effectively mitigating interaction breakdowns. As standard benchmarks lack dense, close-quarter occlusions, this work highlights the critical need for natively captured social dynamics to truly validate HRI perception models.

07.
medRxiv (Medicine) 2026-06-22

Discovering Novel intracranial EEG Biomarkers of Seizure Generating Tissue through Time-Frequency Analysis

Objective: EEG biomarkers for seizure-generating tissue have historically been identified visually, which lacks objectivity and limits utility of automated approaches. For example, high frequency oscillations and interictal epileptiform discharges were promising markers to improve surgical outcomes for refractory epilepsy, but low specificity has hindered clinical implementation, and automated algorithms have not improved this. Methods: We developed Intracranial EEG Pattern Identification and Categorization, an automated, data-driven time-frequency framework for EEG biomarker discovery. It detects transient high-power intracranial EEG waveforms (1-500 Hz) and characterizes them using eight features. In seizure-free patients, waveforms occurring predominantly in resected intracranial EEG channels are candidate biomarkers. Results: In retrospective data from 14 seizure-free post-surgical patients from University of California, Los Angeles, we identified 9 waveform categories strongly associated with resected intracranial EEG channels. These included beta, gamma, and ripple band bursts, sometimes co-occurring with interictal epileptiform discharges; however, many were visually imperceptible in the broadband EEG. Using a support vector machine, we generated a unified classification metric based on these waveforms and tested it on 87 seizure-free subjects from Detroit Medical Center. This metric achieved higher area under the precision-recall curve than six state-of-the-art benchmark algorithms (p

08.
arXiv (CS.AI) 2026-06-19

Too long; didn't solve

arXiv:2604.07593v2 Announce Type: replace Abstract: Mathematical benchmarks consisting of a range of mathematics problems are widely used to evaluate the reasoning abilities of large language models, yet little is known about how their structural properties influence model behaviour. In this work, we investigate two structural length variables, prompt length and solution length, and analyse how they relate to model performance on a newly constructed adversarial dataset of expert-authored mathematics problems. We find that both prompt and solution lengths correlate positively with increased model failure across models. We also include a secondary, exploratory analysis of cross-model disagreement. Under a difficulty-adjusted normalised analysis, both variables retain weak negative associations with realised model separation, slightly stronger for prompt length. Overall, our main robust finding is that structural length is linked to empirical difficulty in this dataset.

09.
arXiv (CS.CV) 2026-06-24

A novel Framework for Open-Vocabulary Multi-Object Recognition using CLIP

To address the limitations of existing open-vocabulary object recognition methods, including high system complexity, substantial training costs, and limited generalization capability, this paper proposes a novel Open-Vocabulary Object Recognition (OVOR) framework based on a streamlined two-stage strategy: object segmentation followed by recognition. The proposed framework eliminates the need for complex retraining procedures and labor-intensive annotation. After extracting object regions, object-level image embeddings and category-level text embeddings are generated using CLIP, enabling recognition over arbitrary vocabularies. To reduce dependence on CLIP and enhance encoding flexibility, we further introduce a CNN/MLP-based approach that extracts convolutional neural network (CNN) feature maps and employs a multilayer perceptron (MLP) to align visual features with text embeddings. The resulting embeddings are then concatenated for cross-modal matching. Finally, object recognition is performed through similarity matching between image and text embeddings. Experiments on COCO, Pascal VOC, and ADE20K demonstrate that CLIP-based image encoding achieves the highest average AP, outperforming current state-of-the-art methods. Meanwhile, the results reveal the potential of CLIP-independent image encoding as a promising alternative for OVOR.

10.
arXiv (quant-ph) 2026-06-11

Additivity and chain rules for quantum entropies via multi-index Schatten norms

arXiv:2502.01611v3 Announce Type: replace Abstract: The primary entropic measures for quantum states are additive under the tensor product. In the analysis of quantum information processing tasks, the minimum entropy of a set of states, e.g., the minimum output entropy of a channel, often plays a crucial role. A fundamental question in quantum information and cryptography is whether the minimum output entropy remains additive under the tensor product of channels. Here, we establish a general additivity statement for the optimized sandwiched Rényi entropy of quantum channels. For that, we generalize the results of [Devetak, Junge, King, Ruskai, CMP 2006] to multi-index Schatten norms. As an application, we strengthen the additivity statement of [Van Himbeeck and Brown, 2025] thus allowing the analysis of time-adaptive quantum cryptographic protocols. In addition, we establish chain rules for Rényi conditional entropies that are similar to the ones used for the generalized entropy accumulation theorem of [Metger, Fawzi, Sutter, Renner, CMP 2024].

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

Conformal Path Reasoning: Trustworthy Knowledge Graph Question Answering via Path-Level Calibration

Knowledge Graph Question Answering (KGQA) offers grounded, interpretable reasoning, but existing methods often fail to provide reliable coverage guarantees over retrieved answers. While Conformal Prediction (CP) offers a principled framework for producing prediction sets with statistical guarantees, prior conformal KGQA methods suffer from two critical pitfalls: violated coverage guarantees due to invalid calibration, and weak score discriminability that yields excessively large prediction sets. We propose Conformal Path Reasoning (CPR), a novel trustworthy KGQA framework built on two key innovations. First, query-level conformal calibration over path-level scores preserves exchangeability to ensure valid coverage guarantees. Second, we introduce the Residual Conformal Value Network (RCVNet), a lightweight module trained via PUCT-guided exploration to learn discriminative path-level nonconformity scores. Extensive experiments show that CPR significantly improves the Empirical Coverage Rate by 45% while reducing prediction set size by 52% on average over conformal baselines across benchmark datasets, highlighting its effectiveness for reliable conformal reasoning over knowledge graphs.

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

Time-Series Foundation Model Embeddings for Remaining Useful Life Estimation

arXiv:2606.11990v1 Announce Type: cross Abstract: Remaining Useful Life (RUL) prediction is essential for industrial predictive maintenance, yet many learning-based approaches rely on extensive feature engineering or large labeled datasets to train task-specific sequence models. In this work, we introduce a lightweight learning approach, in which we leverage a frozen pretrained time-series foundation model (TSFM) and combine it with a small regression head for RUL estimation from multivariate sensor streams. More specifically, we use Chronos-2 as a frozen backbone to extract context window features and train a lightweight regression neural network for RUL prediction. Experiments on real-world industrial sensor data from two device types show that Chronos-2 features consistently improve over recurrent, convolutional, Transformer-based, and gradient-boosting baselines under the same preprocessing and evaluation protocol. We further analyze the impact of context length and find that performance improves significantly with longer histories, indicating that TSFM representation offer a practical and data-efficient alternative for RUL estimation in industrial settings.

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

What sentiment analysis can't see: Measuring whether customers were helped, and what went wrong, across 70,000 support conversations

Most companies read their customer support data at scale using sentiment analysis, which measures how customers sound rather than whether they were satisfied with the result. We tested a richer alternative on 70,450 support conversations from a leading online fundraising platform: alongside tone, we used GPT-5.4 to estimate each customer's satisfaction and to flag whether they reported a concrete problem, then validated all three readings against the 1-to-5 ratings customers left on the conversations they rated. The satisfaction estimate tracked those ratings far better than sentiment did, correlating at 0.47 against 0.36 and flagging unhappy customers with far fewer false alarms. The structured read also sees what sentiment cannot: tone and satisfaction disagree in 44% of conversations, a single "Neutral" label hides everything from quietly satisfied customers to ones who quietly gave up, and the largest group of all is "tolerated friction," customers who are satisfied but still reporting a fixable problem, a standing issue that no sentiment-based dashboard can surface. The broader finding is that LLM-based annotation can capture far more than the tonality of a customer's language, offering strong potential for new business metrics grounded instead in the customer's state (whether they were satisfied) and the cause of their problem extracted directly from the raw textual data of interactions and feedback.

14.
arXiv (quant-ph) 2026-06-16

Adiabatic preparation of a fractional quantum Hall fluid by coherently pumping atoms from a Bose-Einstein condensate

arXiv:2606.15951v1 Announce Type: cross Abstract: We propose a protocol to adiabatically prepare a many-particle fractional quantum Hall fluid of bosonic ultracold atoms exploiting a time-dependent coherent coupling of a strongly interacting atomic state with a large dilute Bose-Einstein condensate. Starting from an empty cloud, atoms with well-defined angular momentum are coherently pumped into the fluid by Raman beams with a Laguerre-Gauss profile. Compared to number-conserving schemes which rely on finite-size-induced topological gaps, we identify an adiabatic path in the Fock space which avoids crossing topological phase transitions and thus maintains a sizable adiabatic gap open at all times. The efficiency of our preparation protocol is numerically assessed for typical experimental parameters up to particle numbers that largely exceed the experimental state-of-the-art. The crucial advantage of including an anharmonic confinement is finally highlighted.

15.
arXiv (CS.CL) 2026-06-16

Who Should Lead Decoding Now? Tracking Reliable Trajectories for Ensembling Masked Diffusion Language Models

Masked Diffusion Language Models (MDLMs) have emerged as a distinct paradigm for sequence generation. As MDLMs become diverse in capabilities and knowledge coverage, an important question is how to combine their knowledge. Toward this, we first investigate the unique decoding dynamics of MDLMs. We find that successful generations exhibit stable confidence dynamics over answer-relevant positions, while unreliable trajectories can often be corrected by injecting promising intermediate states from other models. Guided by this observation, we propose $TIE$ ($T$rajectory-based $I$terative $E$nsembling), a knowledge fusion framework in which MDLMs iteratively identify reliable decoding trajectories and relay them across models. TIE tracks confidence dynamics over answer-relevant positions to determine which model currently follows a more reliable trajectory and selectively transfers partially denoised sequences across models. As the model on the more promising trajectory often changes across denoising steps, TIE allows different models to contribute complementary strengths at different stages of generation. Strong performance across diverse reasoning tasks, along with our analyses, suggests that TIE offers a practical approach to the underexplored problem of MDLM ensembling.

16.
arXiv (CS.CV) 2026-06-17

Advances in 4D Representation: Geometry, Motion, and Interaction

We present a survey on 4D generation and reconstruction, a fast-evolving subfield of computer graphics whose developments have been propelled by recent advances in neural fields, geometric and motion deep learning, as well as 3D generative artificial intelligence (GenAI). While our survey is not the first of its kind, we build our coverage of the domain from a unique and distinctive perspective of 4D representations, to model 3D geometry evolving over time while exhibiting motion and interaction. Specifically, instead of offering an exhaustive enumeration of many works, we take a more selective approach by focusing on representative works to highlight both the desirable properties and ensuing challenges of each representation under different computation, application, and data scenarios. The main take-away message we aim to convey to the readers is on how to select and then customize the appropriate 4D representations for their tasks. Organizationally, we separate the 4D representations based on three key pillars: geometry, motion, and interaction. Our discourse will not only encompass the most popular representations of today, such as neural radiance fields (NeRFs) and 3D Gaussian Splatting (3DGS), but also bring attention to relatively under-explored representations in the 4D context, such as structured models and long-range motions. Throughout our survey, we will reprise the role of large language models (LLMs) and video foundational models (VFMs) in a variety of 4D applications, while steering our discussion towards their current limitations and how they can be addressed. We also provide a dedicated coverage on what 4D datasets are currently available, as well as what is lacking, in driving the subfield forward. Project page:https://mingrui-zhao.github.io/4DRep-GMI/

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

AUTOGATE: Automated Clock Gating via Toggling-Aware LLM-based RTL Rewriting

arXiv:2606.17461v1 Announce Type: cross Abstract: Fine-grain clock gating (FGCG) is among the most effective techniques for reducing dynamic power, yet current FGCG optimization flows remain largely manual. Recent LLM-based RTL optimization approaches remain limited by two key drawbacks: (1) the inability to process long waveform traces spanning millions of cycles, and (2) the difficulty of scaling optimization to large hierarchical codebases while preserving correctness. In this work, we present AUTOGATE, the first agentic framework for industry-grade RTL power optimization, enabling workload-aware clock-gating optimization across large hierarchical codebases. AUTOGATE introduces a Machine Learning (ML)-LLM co-design that bridges waveform-level analysis and RTL rewriting. Specifically, we design an ML-based clustering algorithm that distills raw toggling traces into compact, structured representations that guide LLM-based RTL rewriting. This enables accurate identification and application of clock-gating opportunities without requiring LLMs to directly process raw waveform data. To enhance scalability, AUTOGATE employs a hierarchical multi-agent architecture that decomposes large designs into independently optimizable modules, enabling coordinated optimization across deep design hierarchies. We evaluate AUTOGATE on a diverse set of designs ranging from small RTL designs to large industrial-grade codebases. Experimental results show that AUTOGATE consistently reduces dynamic power relative to baselines. Across the small-design suite, AUTOGATE reduces dynamic power by 49.31% on average. On industry-scale designs, it achieves 19.34% and 7.96% dynamic power reductions on NVDLA and BlackParrot, respectively, and up to 6.86% on highly optimized proprietary production designs.

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

PermaVid: Consistent Video Generation Across Edits via Disentangled Context Memory

Consistent video generation under editing operations requires persistence: when edits modify scene appearance or layout, subsequent generations should remain coherent across time and viewpoints. However, existing memory designs struggle to maintain long-term consistency after such modifications, as stored contexts may become outdated or invalid. To address this, we propose PermaVid, a novel framework built upon a multi-modal context memory that disentangles spatial context into semantic appearance and geometric structure, together with an edit-aware memory update and retrieval strategy that keeps memory evolution aligned with subsequent observations. Specifically, we develop two complementary memory banks: an RGB context memory that captures appearance-aware observations while implicitly encoding geometry, and a depth context memory that preserves geometry-only structure disentangled from semantics. Building on this design, we introduce a memory-guided video generation model that performs multi-modal feature fusion under reference conditions drawn from mixed-modality memory contexts. Experiments demonstrate that our method maintains strong long-term semantic and structural consistency after edits, significantly outperforming state-of-the-art methods.

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

CoreMem: Riemannian Retrieval and Fisher-Guided Distillation for Long-Term Memory in Dialogue Agents

Personalized dialogue agents require continuous long-term memory to maintain coherent interactions across multiple sessions. However, deploying these capabilities on consumer-grade hardware (e.g., 8 GB VRAM edge devices) introduces severe memory and compute bottlenecks. Existing systems typically rely on isotropic cosine similarity for retrieval and heuristic rules for context compression. These approaches lack a unified theoretical foundation, frequently suffering from the hubness problem in high-dimensional retrieval and syntactic fragmentation during compression. To overcome these limitations, we propose CoreMem, a resource-efficient edge-cloud memory architecture fundamentally unified by information geometry. First, Riemannian retrieval replaces cosine matching with a locally adaptive Fisher-Rao metric, effectively penalizing hub memories via Mahalanobis distance with O(Ndr) Woodbury acceleration for real-time search. Second, Fisher-guided discrete token distillation (FDTD) introduces a hierarchical sentence-to-token compression mechanism. It derives sensitivity scores from Fisher information traces, providing a principled compression-KL tradeoff augmented with explicit structural syntax protection. Evaluated on the LOCOMO and LongMemEval-S benchmarks, CoreMem achieves strong accuracy improvements, yielding substantial gains in Open-domain (+4.51 pp) and Temporal (+4.17 pp) reasoning. Extensive profiling confirms that CoreMem operates seamlessly within a strict 8 GB VRAM budget, successfully bridging the gap between resource-constrained edge devices and the demand for theoretically grounded, lifelong memory agents.

20.
arXiv (math.PR) 2026-06-16

Steady-State Approximation Error of Heterogeneous Mean-Field Models

Authors:

arXiv:2606.09022v2 Announce Type: replace Abstract: This paper studies heterogeneous mean-field models in which agent parameters are sampled from a population distribution. We establish an $O(1/M)$ bound on the steady-state mean-square error between the occupancy measure of the $M$-agent system and the corresponding annealed mean-field equilibrium. The analysis extends Stein's method for homogeneous mean-field models and reveals a fundamental difference between homogeneous and heterogeneous systems. While stability of the mean-field dynamics is sufficient in the homogeneous setting, heterogeneous systems further require uniform robustness of the occupancy dynamics with respect to perturbations of the initial condition. The results are illustrated through a heterogeneous SIS epidemic model.

21.
arXiv (math.PR) 2026-06-11

Patterned matrices with random walk entries

arXiv:2512.04612v3 Announce Type: replace Abstract: It is well known that the weak limit of a suitably scaled continuous-time random walk (CTRW) is the Brownian motion. We investigate the convergence of certain patterned random matrices whose entries are independent CTRWs and their time-changed versions, in a non-commutative probability framework. For the Wigner link function, the limits are free Brownian motion and its time-changed version driven by an inverse stable subordinator. For the symmetric circulant and the circulant with CTRW entries, we use their explicit eigenvalue expressions to define some empirical processes that converge weakly to a Brownian motion and a complex Brownian motion, respectively. For matrices with iid entries, and for elliptic matrices, the algebraic limits are equal in $*$-distribution to processes whose marginals are circular and elliptic variables, respectively. A random time-changed variant of these results is also established.

22.
medRxiv (Medicine) 2026-06-22

Accounting for uncertainty in the expected treatment effect substantially increases the sample size required for randomised trials: implications for the feasibility of clinical trials in anaesthesia and critical care

Background Multicentre trials in anaesthesia and critical care report low rates of statistically significant differences. This finding may partly reflect conventional sample size methods, which assume a fixed treatment effect. Assurance methods use a design prior to represent uncertainty in the expected treatment effect, which may provide a more realistic way of estimating sample sizes. Methods We calculated power curves across a range of effect sizes, design priors, and sample sizes using frequentist and Bayesian assurance methods and compared the sample sizes required to achieve 80% and 90% power to the conventional method. We standardised the design priors across effect sizes using the coefficient of variation. We derived a theoretical limit for achievable power. We validated a normal approximation to the Bayesian posterior distribution. Results Frequentist and Bayesian assurance methods produced similar power curves across all scenarios. At a coefficient of variation of 0.5 - reflecting realistic prior uncertainty in the expected effect size - both methods required sample sizes that were approximately 1.5 to 3.5 times larger than the conventional method. The theoretical power limit depends only on the coefficient of variation of the design prior and holds true across all effect sizes. The normal approximation to the Bayesian posterior distribution matched the results obtained from Markov chain Monte Carlo sampling. Conclusions Incorporating clinical uncertainty in the expected effect size substantially increases the sample size required to achieve adequate power, which has important implications for the feasibility of randomised trials in anaesthesia and critical care.

23.
Nature (Science) 2026-06-24

Zero-shot design of drug-binding proteins via neural iterative selection−expansion

Authors:

The design of proteins that bind to small molecules has been challenging because it requires simultaneous optimization of the protein sequence, protein structure and ligand conformation1–7. Current deep-learning algorithms have struggled to navigate this landscape, precluding the zero-shot design of binders. Here we show that by combining two neural networks in an iterative design algorithm, small-molecule binding proteins can be created from scratch with high accuracy. We trained a graph neural network—ligand-aware sequence engineering message-passing neural network (LASErMPNN)—to design compatible protein sequences for an input protein backbone and docked ligand. We paired  LASErMPNN with a structure predictor that models a three-dimensional protein–ligand complex for an input protein sequence and ligand identity. The closed-loop iteration of these reciprocal networks optimized sequence–structure–ligand compatibility, and outperformed a comparable design loop using a physics-based energy function. We used our strategy, termed neural iterative selection–expansion (NISE), to design proteins that, using different folds, specifically bind to two chemically distinct small-molecule drugs, exatecan and apixaban, with success rates of 100% and 83%, respectively. The tightest NISE binders had nanomolar-to-picomolar affinities, surpassing those of the next-leading method by 70-fold for exatecan and nearly 10,000-fold for apixaban. LASErMPNN then suggested two amino-acid substitutions that improved the affinity of the tightest exatecan binder by 100-fold without any experimental input. The optimized binder protected the labile lactone ring of exatecan from hydrolysis for days. Our work describes a general recipe for using neural networks to automate the design of small-molecule binding proteins for applications in drug delivery, sensing and catalysis.  By pairing two neural networks in an iterative optimization algorithm, small-molecule binding proteins can be designed from scratch with high accuracy, affinity and success rates, showing promise for applications in drug delivery and sequestration.

24.
arXiv (quant-ph) 2026-06-19

Quantum Algebraic Diversity: Single-Copy Density Matrix Estimation via Group-Structured Measurements

arXiv:2604.03725v3 Announce Type: replace Abstract: We extend the algebraic diversity (AD) framework from classical signal processing to quantum measurement theory. The Quantum Algebraic Diversity (QAD) Theorem establishes that a group-structured positive operator-valued measure (POVM) applied to a single copy of a quantum state produces a full-rank, group-averaged density matrix estimator whose eigenbasis and eigenvalue ordering track those of the true density matrix, with a bias toward the symmetrized state, analogous to the classical recovery of covariance eigenstructure from a single observation. We establish a Classical-Quantum Duality Map connecting classical covariance estimation to quantum state tomography, and an Optimality Inheritance Theorem showing that classical group optimality transfers to quantum settings via the Born map within the group-averaged family. SIC-POVMs are identified as AD with the Heisenberg-Weyl group and mutually unbiased bases as AD with the Clifford group, revealing the hierarchy $\mathrm{HW}(d) \subseteq \mathcal{C}(d) \subseteq S_d$ that mirrors the classical $\mathbb{Z}_M \subseteq G_{\min} \subseteq S_M$. The double-commutator eigenvalue theorem gives polynomial-time adaptive POVM selection. A worked qubit example shows the group-averaged estimator from a single computational-basis measurement, averaged over a matched $\mathbb{Z}_2$ group, reaching fidelity 0.99 where standard single-basis tomography gives a rank-1 estimate of fidelity 0.80. Monte Carlo simulations for $d = 2$ to $13$ confirm fidelity above 0.90 from a single outcome while standard fidelity degrades as $\sim 1/d$. The growing ratio reflects collapse of the rank-1 standard estimator, not fewer copies per parameter: the biased single-copy estimator reduces the number of distinct measurement settings, not the per-parameter sampling cost, and a genuine copy reduction holds only under exact symmetry.

25.
arXiv (CS.CL) 2026-06-19

IHUBERT: Vector-Based Semantic Deduplication and Domain-Balanced Pretraining for Persian Resources

Persian pretrained language models (PLMs) are still limited by the scarcity of large-scale, high-quality pretraining corpora and by insufficient evaluation beyond standard classification and NER tasks. We present IHUBERT, a monolingual Persian PLM trained from scratch with the RoBERTa-base encoder (125M parameters) on a 45 GB curated subset of the Sepahr-Danesh collection (about 7-8B tokens). To improve corpus quality and reduce redundancy, we employ a multi-stage preprocessing pipeline that includes normalization, exact and near-duplicate removal, anonymization, and vector-database-based semantic deduplication for distribution balancing control across domains and registers. We additionally train a 139k-vocabulary BPE tokenizer on the full pretraining corpus to better capture Persian morphology and orthographic variation. IHUBERT is evaluated on seven Persian NLU benchmarks covering NER, sentiment analysis, topic classification, NLI, extractive question answering, and relation extraction, using task-standard metrics (entity-level F1, Macro-F1, EM/F1). IHUBERT achieves its strongest gains on extractive QA, ranking first on both PQuAD (F1 88.3542) and ParsiNLU-RC (F1 49.0987), and attains the best result on FarsTail (Macro-F1 0.8350). On NER and topic classification, it remains competitive (e.g., 0.8308 F1 on ParsTwiNER; 0.7953 Macro-F1 on DigiMag), while relation extraction remains the main remaining gap (0.6684 Macro-F1 on PERLEX). A controlled tokenizer ablation on the IHUBERT pretraining corpus shows that BPE yields slightly lower subword fragmentation than WordPiece at matched vocabulary size, supporting our tokenization design. Overall, IHUBERT advances Persian language modeling through semantically curated large-scale pretraining and broad evaluation across both classification and comprehension-oriented tasks.