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01.
arXiv (CS.AI) 2026-06-18

TxBench-PP: Analyzing AI Agent Performance on Small-Molecule Preclinical Pharmacology

Authors:
Hannah Le↗Ramesh Ramasamy↗Alex Urrutia↗Mahsa Yazdani↗Tim Proctor↗Kenny Workman↗

arXiv:2606.19245v1 Announce Type: new Abstract: Artificial intelligence (AI) agents promise to accelerate drug discovery by compressing interpretation and decision-making loops, but practical deployment requires trusted evaluation on realistic program decisions. We introduce TherapeuticsBench Preclinical Pharmacology (TxBench-PP), a verifiable benchmark for small-molecule preclinical pharmacology and the first focused slice of a broader TherapeuticsBench effort across drug-discovery stages and therapeutic modalities. TxBench-PP tests whether agents can recover accurate conclusions from real-world assay data rather than memorized facts from literature. The benchmark contains 100 evaluations indexed by program stage, assay type, and task structure, spanning mechanism-of-action (MoA) and pharmacodynamic (PD) reasoning, compound-target engagement, causal target validation, developability and safety, and translational efficacy. Agents receive realistic workflow snapshots, inspect files in a coding environment, and return structured answers graded deterministically. Across 16 model-harness configurations, comprising 11 models and 4,800 trajectories, no system reliably recovered preclinical pharmacology decisions. The strongest configuration, Claude Opus 4.8 / Pi, passed 59.3\% of endpoint attempts (178/300; 95\% CI, 51.1-67.6), followed by GPT-5.5 / Pi at 55.3\% (166/300; 47.0-63.6).

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02.
bioRxiv (Bioinfo) 2026-06-11

STITCH links cellular morphology and gene expression in spatial transcriptomics

Authors:
Kumar↗Shi↗Vallius↗Day↗C.-P↗Absil↗P.- A↗Srivastava↗Hannenhalli↗Gopalan↗

In situ spatial (ISS) sequencing can uncover co-variation between cellular morphology and gene expression in vivo. However, a principled and interpretable mathematical representation of morphology has not yet been applied in this context. In particular, current deep learning-based representations of cell images confound a cell's shape with its size. We present an interpretable representation of cellular boundary contours, based on tangent principal component analysis (TPCA) in a Kendall shape manifold, that captures size-independent contour shape features. This approach successfully recovers shape-perturbing genes in an RNAi screen than a previous metric geometry-based approach. We build on TPCA to develop STITCH (Shape-TranscriptomIc Correlation and Harmonization), an approach to reveal covariation between cell morphology with gene expression in ISS datasets. In a Xenium dataset, STITCH outperforms a deep learning-based approach in both recovering the layered organization of keratinocytes and a spatial gradient in nuclear eccentricity. Across samples in a melanoma CosMx dataset, STITCH reproducibly associates elongated and triangular fibroblasts with proximity to malignant cells and myofibroblast-like transcriptional program. Finally, STITCH independently recovers a known link between mesenchymal-like malignant cell states and increased cell area in two melanoma cohorts. STITCH can thus yield interpretable morphology-transcriptome relationships across cell types, patients, and spatial transcriptomics platforms.

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03.
arXiv (quant-ph) 2026-06-24

A Quantum Non-Gaussianity Criterion Based on Photon Correlations $g^{(2)}$ and $g^{(3)}$

Authors:
Christoph Hotter↗Clara Henke↗Cornelis Jacobus van Diepen↗Peter Lodahl↗Anders S{\o}ndberg S{\o}rensen↗

arXiv:2511.08488v2 Announce Type: replace Abstract: Quantum non-Gaussian states, which cannot be written as mixtures of Gaussian states, are necessary to achieve a quantum advantage in continuous variable systems. They represent an important benchmark for the realization of an advanced quantum light source, as they cannot be made by simple means such as displacement and squeezing. We introduce an attenuation-resistant sufficient criterion for quantum non-Gaussian states based on the second- and third-order correlation functions, $g^{(2)}$ and $g^{(3)}$. The general non-linear bound for classical mixtures of Gaussian states is $\sqrt{g^{(3)}} + 3 \sqrt{g^{(2)}} \geq 2$. Any mixture of Gaussian states must fulfill this inequality, thus, the violation of it represents a direct confirmation of quantum non-Gaussianity. We experimentally show the non-Gaussianity of the state produced by a quantum dot single-photon source, where we obtain $\sqrt{g^{(3)}} + 3 \sqrt{g^{(2)}} = 0.174 (13)$, which represents a statistical significance of more than $100$ standard deviations.

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04.
arXiv (CS.CL) 2026-06-16

HK-LegiCoST: Leveraging Non-Verbatim Transcripts for Speech Translation

Authors:
Cihan Xiao↗Henry Li Xinyuan↗Jinyi Yang↗Dongji Gao↗Matthew Wiesner↗Kevin Duh↗Sanjeev Khudanpur↗

We introduce HK-LegiCoST, a new three-way parallel corpus of Cantonese-English translations, containing 600+ hours of Cantonese audio, its standard traditional Chinese transcript, and English translation, segmented and aligned at the sentence level. We describe the notable challenges in corpus preparation: segmentation, alignment of long audio recordings, and sentence-level alignment with non-verbatim transcripts. Such transcripts make the corpus suitable for speech translation research when there are significant differences between the spoken and written forms of the source language. Due to its large size, we are able to demonstrate competitive speech translation baselines on HK-LegiCoST and extend them to promising cross-corpus results on the FLEURS Cantonese subset. These results deliver insights into speech recognition and translation research in languages for which non-verbatim or ``noisy'' transcription is common due to various factors, including vernacular and dialectal speech.

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05.
arXiv (quant-ph) 2026-06-19

Exclusion Statistics as a Thermodynamic Resource in Quantum Heat Engines

Authors:
Sampurna Karmakar↗Aziz Hasan↗Sourin Das↗

arXiv:2606.19310v1 Announce Type: cross Abstract: The maximum power extractable from a quantum thermoelectric heat engine operating with free fermion carriers is bounded by the universal Whitney limit, $P_{fermion}^{\max} \simeq 0.0321\pi^2 k_B^2(T_L-T_R)^2/h$. We demonstrate that this bound is not fundamental to quantum heat engines but is instead an artifact of fermionic statistics. Within the nonlinear Landauer-B\"{u}ttiker framework, a bosonic working medium yields a strictly enhanced universal maximum power, $P_{boson}^{\max} = (\ln 2)^2\, k_B^2(T_L-T_R)^2/h$, exceeding the fermionic limit by a factor of $(\ln 2)^2/(0.0321\pi^2) \approx 1.52$. We propose magnon transport through a ferromagnetic spin chain as an experimentally viable bosonic realization. Incorporating Haldane fractional exclusion statistics with parameter $g$ provides a continuous interpolation between the bosonic ($g = 0$) and fermionic ($g = 1$) limits, revealing a monotonic enhancement of maximum power for $g < 1$ at reduced bias cost. These results establish quantum statistical exclusion as a previously unrecognized and independently tunable thermodynamic resource, opening performance regimes inaccessible to conventional carrier-engineering approaches.

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

Learning New Tasks via Reusable Skills: Skill-Compositional Experts for Embodied Continual Learning

Authors:
Shuaike Zhang↗Shaokun Wang↗Haoyu Tang↗Jianlong Wu↗Liqiang Nie↗

Embodied Continual Learning (ECL) aims to enable robots to continually acquire new manipulation tasks while retaining previously learned behaviors under closed-loop control. Compared with conventional continual learning, ECL suffers from more severe catastrophic forgetting. Feature drift accumulated under closed-loop control progressively propagates through sequential decision-making, leading to degradation of previously learned behaviors. A key challenge in ECL lies in structured skill reuse across continually evolving tasks, since existing methods primarily focus on skill learning without explicitly organizing them for coherent task execution. To address this issue, we propose SCE, a Skill-Compositional Experts framework for ECL. SCE builds a skill base via Compositional Skill Grounding (CSG), which decomposes task demonstrations into reusable skills. Based on this, Dual Execution-and-Transition Experts (DETE) enable new task learning through skill composition, where one branch ensures skill execution and the other supports transitions between skills for coherent behavior. Experiments on LIBERO benchmarks and real-world manipulation tasks demonstrate that SCE consistently improves retention and overall task performance. Further feature drift analyses and ablation studies verify the effectiveness of our method. Project website: https://eqcy.github.io/sce/.

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07.
arXiv (quant-ph) 2026-06-19

A Finite-Volume Scheme for the Continuum Extrapolation of Lattice Step-Scaling in (2+1)D Hamiltonian U(1) Gauge Theory

Authors:
Alessio Negro↗Emil Otis Rosanowski↗Lena Funcke↗Timo Jakobs↗Karl Jansen↗Paul Ludwig↗Carsten Urbach↗

arXiv:2606.20029v1 Announce Type: cross Abstract: We propose a finite-volume scheme to perform controlled continuum extrapolations of the lattice step-scaling function, a key ingredient for determining the running coupling in a Hamiltonian lattice gauge theory in small volumes. As a testbed, we employ a dual Hamiltonian formulation of pure U(1) gauge theory in (2+1) dimensions and an operator basis that remains efficient toward weak coupling. We describe the implementation of static external charges on the spatial lattice and study, using matrix product states, the resulting confining string, from which we extract the static potential and a force-based renormalized coupling. Using the proposed finite-volume scheme, we demonstrate a stable continuum limit of the step-scaling function on the lattice sizes accessible to present Hamiltonian simulations. The method is readily extendable to other gauge groups and dimensions, providing a pathway toward Hamiltonian step-scaling studies in other theories.

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08.
arXiv (quant-ph) 2026-06-17

The Standard Model, The Exceptional Jordan Algebra, and Triality

Authors:
Latham Boyle↗

arXiv:2006.16265v2 Announce Type: replace-cross Abstract: Jordan, Wigner and von Neumann classified the possible algebras of quantum mechanical observables, and found they fell into 4 "ordinary" families, plus one remarkable outlier: the exceptional Jordan algebra. We point out an intriguing relationship between the complexification of this algebra and the standard model of particle physics, its minimal left-right-symmetric $SU(3)\times SU(2)_{L}\times SU(2)_{R}\times U(1)$ extension, and $Spin(10)$ unification. This suggests a geometric interpretation, where a single generation of standard model fermions is described by the tangent space $(\mathbb{C}\otimes\mathbb{O})^{2}$ of the complex octonionic projective plane, and the existence of three generations is related to $SO(8)$ triality.

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09.
bioRxiv (Bioinfo) 2026-06-11

GeroQubit: a lightweight, honesty-first de-novo design platform for geroscience-native small molecules with calibrated uncertainty

Authors:
Swetha↗

Computational molecule generation has outpaced its own credibility. We present GeroQubit, a GPU-free de-novo design platform that organizes candidates along a target x tissue x hallmark model and reports every signal alongside its measured baseline. We treat our tissue aging-signature readout as a mechanistic structural prior that we explicitly disclose is not validated against lifespan, and we surface efficacy only through a structure-to-lifespan k-NN whose weak but real signal (leave-one-out rho ~ 0.145) is wrapped in empirically-calibrated conformal intervals (90% target, 90.3% measured coverage). On a held-out retrospective recovery of ~1,940 ChEMBL binders against decoys, the score reaches ROC-AUC 0.945 with ~20x enrichment at 1% (BEDROC 0.91) and survives a scaffold-disjoint split - yet we report that it collapses to near-random (AUC 0.62) on genuinely novel chemotypes. Molecules are assembled reaction-first, so every candidate carries a verified synthetic route and atom-level synthon provenance; ADMET is handled as a multi-objective Pareto problem. We frame the disclosed weak signals and the hard-case failures not as flaws but as the honest, decision-useful output the field's own critics demand.

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10.
arXiv (CS.AI) 2026-06-16

Mojo: A Promising Tool for Scalable Financial AI Efficiency

Authors:
Henry Han↗

arXiv:2606.16059v1 Announce Type: cross Abstract: For thirty years, quantitative finance has paid a costly two-language tax: models researched in Python are rewritten in C++ for production, often introducing numerical discrepancies. GPU-accelerated deep learning exacerbates this problem, as nondeterministic floating-point reductions can produce drift in long backtests, challenging regulatory reproducibility and auditability expectations. This article surveys Mojo, Modular's 2026 Python-like systems language, as a structural response for capital markets engineering. While closing the Python-to-C++ performance gap, Mojo uniquely combines native interoperability with the low-level systems control required to construct bit-exact deterministic kernels. Its MLIR compilation infrastructure further allows a single codebase to target scalar, SIMD, multicore, and GPU execution, reducing the translation bottleneck between research and production. We benchmark four core financial AI workloads: Monte Carlo option pricing, LLM sentiment inference, multi-asset backtesting, and portfolio Value at Risk. On Apple Silicon, Mojo demonstrates 20x to 180x speedups over pure Python on directly measured kernels; larger-scale GPU workload results are projections calibrated from published benchmarks. Alongside transparent performance data, we introduce mojo-deterministic, an open-source library of reproducible reduction kernels, and provide a candid assessment of the problems Mojo does and does not yet solve.

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

RepNet: Tackling spectral bias in deep neural networks via parameter reparameterization

Authors:
Yong Wang↗Tao Zhou↗Xuhui Meng↗

arXiv:2606.16575v1 Announce Type: new Abstract: Deep neural networks (DNNs) have achieved remarkable success in scientific computing, yet they often suffer from spectral bias in capturing oscillatory and multiscale behaviors. In this study, we investigate this limitation by examining the failure of shallow ReLU neural networks in fitting high-frequency functions. This observation identifies two important factors in resolving rapid oscillations: the initial slope scale and the distribution of partition points induced by the networks. Motivated by this analysis, we propose RepNet, a reparameterized DNN model for ReLU and tanh networks designed for high-frequency and multiscale problems. The key idea is to reparameterize the weights and biases in the first hidden layer, which enables effective control of the initial slope scale and provides an appropriate distribution of the initial partition points. Furthermore, treating the reparameterized weights and biases as trainable parameters allows the DNN to achieve adaptive frequency scaling during training. In addition, we derive quantitative estimates for the output and slope magnitudes of the reparameterized DNN to guide the initialization of the proposed method. Numerical experiments, including multiscale one- and four-dimensional function approximation, forward and inverse PDE problems in combination with physics-informed neural networks (PINNs), and operator learning, demonstrate that RepNet improves the predicted accuracy of vanilla DNNs in capturing highly oscillatory features with slightly additional computational cost. These results indicate that RepNet provides an effective and flexible approach for overcoming spectral bias and applying DNNs to multiscale problems.

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

FISHER: A Foundation Model for Multi-Modal Industrial Signal Comprehensive Representation

Authors:
Pingyi Fan↗Anbai Jiang↗Shuwei Zhang↗Xinhu Zheng↗Zhiqiang Lv↗Bing Han↗Wenrui Liang↗Junjie Li↗Wei-Qiang Zhang↗Yanmin Qian↗Xie Chen↗Jia Liu↗…

arXiv:2507.16696v3 Announce Type: replace-cross Abstract: Industrial signal analysis is hindered by severe data heterogeneity, which we characterize as the M5 problem. Existing solutions rely on specialized models that lack robustness and scalability, while large-scale pre-training has rarely been investigated in this area. In this work, we derive a prioritized roadmap for the M5 problem and propose FISHER, a Foundation model for multi-modal Industrial Signal compreHEnsive Representation. To address the foremost multi-sampling-rate problem, FISHER utilizes a novel sub-band modeling approach that treats sampling rate increments as concatenated sub-band information, enabling the adaptive usage of full signal bandwidth without resampling. FISHER is pre-trained by teacher-student self-distillation over external audio and music data. We also establish the RMIS benchmark, comprising 19 datasets across four modalities. In the experiment, FISHER outperforms 24 state-of-the-art series encoders (up to 2B) with much smaller sizes (up to 16x), showcasing groundbreaking diagnostic accuracy and remarkable versatility. We further demonstrate that 1) seamless adaptation to variable sampling rates is the key to generalization 2) audio and music data provide better temporal variability, which is essential for pre-training. Both FISHER and RMIS are open-sourced.

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13.
arXiv (CS.CL) 2026-06-16

Spokes: Optimizing for Diverse Pretraining Data Selection

Authors:
Clarence Lee↗Yejin Choi↗Luke Zettlemoyer↗Pang Wei Koh↗Hai Leong Chieu↗

Diversity plays a critical role in data selection, improving performance under fixed data budgets by reducing redundancy and repetition. However, optimizing for diversity is inherently challenging, as it is a set-level property that depends on interactions between data points rather than individual examples. As a result, existing approaches typically rely on proxies or approximations, which often fail to ensure sufficiently diverse subsets. In this work, we directly optimize diversity by introducing a probabilistic diversification framework based on the G-Vendi score, optimized via exponentiated gradient descent. Our method produces subsets that are substantially more diverse than those obtained via random sampling, achieving a +489 increase in G-Vendi score on a 500k-sample subset. We evaluate our approach on FineWeb and DCLM, where it consistently outperforms existing methods. Notably, SPOKES (diversity-only) improves average downstream performance by +0.4 and +0.5 points over random sampling on DCLM and FineWeb, respectively. More importantly, jointly optimizing for both quality and diversity yields the strongest results: SPOKES achieves gains of +1.5 and +1.4 points on DCLM and FineWeb, outperforming all baselines, including semantic deduplication and quality filtering.

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14.
arXiv (CS.CV) 2026-06-18

Spatially Stratified Distillation for Heterogeneous Radar Place Recognition

Authors:
Sagun Singh Shrestha↗Samuel Harding↗Abdelwahed Khamis↗Saimunur Rahman↗Peyman Moghadam↗

Scalable, all-weather place recognition increasingly relies on heterogeneous radar place recognition to bridge diverse hardware platforms. A notable application is matching queries from cost-effective 4D automotive radars against high-fidelity reference maps built by dense spinning radars. This process is fundamentally limited by the extreme sparsity (and narrow field-of-view) of the 4D sensor, which captures only a fraction of the structural density present in the spinning radar database. Prior efforts address this issue by unifying different radar signals. That is, projecting both signals into a common representational space. Yet, they suffer performance degradation in multi-session environments. In this paper, we propose spatially-stratified distillation (SSD); a strategy that replaces standard uniform distillation with an asymmetric spatial alignment derived directly from physical radar returns. In regions where both radars exhibit overlapping returns, SSD enforces strong feature alignment. Crucially, in sparse regions where the 4D student lacks returns but the teacher contains valid structure within the shared field of view, SSD applies heavily discounted distillation weights. Extensive evaluations of the recent HeRCULES dataset demonstrate that SSD significantly outperforms prior place recognition methods, achieving state-of-the-art results on its challenging dynamic sequences.

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15.
arXiv (math.PR) 2026-06-17

The Erdős-Hajnal High-Girth Subgraph Conjecture Holds in the Polynomial Chromatic-Sparsity Regime

Authors:
Eric Li↗

arXiv:2606.17901v1 Announce Type: cross Abstract: For a graph $G$ put $h_r(G)=\max{\chi(H):H\subseteq G,\operatorname{girth}(H)\ge r}.$ Erdős and Hajnal asked whether $h_r(G)\to\infty$ as $\chi(G)\to\infty$, for every fixed $r\ge4$. We prove this in every fixed polynomial edge-density regime: for all $r\ge4$, $k\ge2$, $P,C>0$, there is $M=M_{r,k}(P,C)$ such that $\chi(G)\ge M,\ e(G)\le C\chi(G)^P\Longrightarrow h_r(G)\ge k.$ Quantitatively, after replacing $P$ by $P\vee2$ and $C$ by $C\vee2$, $M_{r,k}(P,C)\le \exp!\left(O_{r,k}\bigl((P+2+\log(C\vee2))^2\bigr)\right),$ and consequently the same conclusion holds throughout the quasi-polynomial range $e(G)\le \exp\bigl(C_0(\log\chi(G))^a\bigr),\ 1 < a < 3/2,$ for all sufficiently large $\chi(G)$. In each fixed polynomial-density regime we also obtain $f_{P,C}(k,r)\le k^{O_{r,P,C}(1)}.$ The proof combines a chromatic-defect random extraction lemma, compact and near-quadratic sparse-core bases, and a peeling/thinning bootstrap increasing the admissible edge exponent by $1/(r-1)$. We also prove structural saturation results for possible counterexamples, including Moore-strength exact-cycle packings and quadratic saturation in projected colour-pair space. Finally, writing $h_r^{\mathrm f}(G)=\max{\chi_{\mathrm f}(H):H\subseteq G,\operatorname{girth}(H)\ge r},$ we develop a fractional random-extraction framework based on Mohar-Wu preservation. We prove sufficient cheap-cycle-killing criteria and verify them for several structured families, including clique-organised families, line graphs of incidence graphs of equal-order generalized quadrangles and generalized hexagons, and the Bohman-Keevash tracking-time triangle-free-process graph. We also isolate a density-free obstruction that any proof using this fractional surgery route must overcome.

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

Understanding LLMs in Title-Abstract Screening: From Disagreements to Recommendations

Authors:
Mika M\"antyl\"a↗Patricia Matsubara↗Katia Romero Felizardo↗Miikka Kuutila↗Marco Gerosa↗Savio de Sousa Sampaio↗Tayana Conte↗Igor Steinmacher↗

arXiv:2606.17588v1 Announce Type: cross Abstract: Several studies have examined the use of large language models (LLMs) for title-abstract screening in systematic reviews (SRs), reporting mixed accuracy. However, questions of reliability remain largely unaddressed. In this study, we go beyond quantitative LLM-human agreement metrics and qualitatively investigate how and why LLMs fail. We also propose actionable recommendations. We analyzed disagreements between LLMs and researchers across six software engineering SRs and over 1,000 primary study papers. For each SR, papers were screened independently by human experts and LLMs in zero-shot mode, resulting in Kappa values ranging from 0.52 to 0.77. Qualitative analysis suggests that human-LLM disagreement results from recurring, identifiable causes, such as boundary ambiguity in key terms, keyword overemphasization, and incorrect topic inference. Based on these findings, we propose recommendations such as validating semantic understanding before deployment, running multiple LLMs, and focusing validation efforts on borderline cases. Future studies are needed to validate the impact of our recommendations, and community efforts are needed to develop normative guidelines on LLM usage in SRs.

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17.
arXiv (quant-ph) 2026-06-19

Transfer-matrix functions for algebraically decaying interactions in variational infinite matrix product states

Authors:
Qi Yang↗

arXiv:2606.20522v1 Announce Type: cross Abstract: Variational infinite matrix product state (iMPS) calculations usually make Hamiltonians with algebraically decaying interactions compatible with standard MPO algorithms by first replacing the target Hamiltonian with a finite-pole sum-of-exponentials surrogate, thereby introducing a Hamiltonian-representation residual. We formulate the fixed-$D$ variational energy without introducing such a surrogate. For a fixed finite-$D$ MPS, the algebraic tail can be summed directly through the connected transfer matrix: the tail $e^{\mathrm{i} Qr}/r^\alpha$ is represented by the matrix function $F_{\alpha,Q}(\widetilde{T}_A)$, with $F_{\alpha,Q}(z)=\operatorname{Li}_\alpha(e^{\mathrm{i} Q}\,z)/z$. We evaluate the resulting matrix-function action using a Krylov method and obtain stable gradients by combining a Fréchet adjoint with implicit fixed-point differentiation. Benchmarks on long-range free fermions and the inverse-square Heisenberg family, including the Haldane–Shastry point, validate the transfer-matrix-function formulation. A long-range Ising-chain calculation illustrates a practical consequence of avoiding a finite-pole Hamiltonian representation. At a fixed, independently known critical field, finite-pole surrogate Hamiltonians can bias a critical diagnostic away from criticality, whereas the matrix-function calculation retains the expected critical signatures of the target algebraic Hamiltonian.

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19.
PLOS Computational Biology 2026-06-05

Heuristic multi-site optimization for protein sequence design using Masked Protein Language Models

Authors:
Lijuan Wang↗

by Lijuan Wang, Yuze Wang, Chen Qiu, Liwei Xiao, Xianliang Liu, Junjie Chen Protein sequence design for tailored functional properties is a fundamental task in protein engineering, with critical applications in drug discovery and therapeutic development. Efficient navigation of the combinatorial vastness of protein sequence space to identify functional variants remains a formidable challenge. Conventional approaches, which predominantly rely on template-based local search or single-residue mutagenesis, are constrained by their susceptibility to local optima and their potential risk of destabilizing native structural stability. In this study, we introduce ProtHMSO, a heuristic multi-site optimization framework leveraging masked protein language models (ProtLMs) for context-aware sequence exploration. ProtHMSO mimics natural evolutionary mechanisms by employing ProtLM-derived substitution probabilities to guide heuristic searches for synergistic mutations, thereby constraining combinatorial search spaces through evolutionary and biophysical priors. ProtHMSO is further applied to replace the exploration strategies in genetic algorithms (GAs) and Monte Carlo tree search (MCTS) for improving their convergence efficiency. Benchmark experiments demonstrate that protein sequences generated by ProtHMSO exhibit superior functional performance and closer alignment with natural sequence distribution, compared with state-of-the-art methods. These advancements highlight that ProtHMSO has strong potential and compatibility to accelerate functional protein discovery, offering a robust framework for efficient and context-aware exploration of protein sequence space.

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20.
arXiv (math.PR) 2026-06-11

Sure-almost-sure and Sure-limit-sure Window Mean Payoff in Markov Decision Processes

Authors:
Pranshu Gaba↗Shibashis Guha↗

arXiv:2605.12191v2 Announce Type: replace-cross Abstract: Given rationals $\alpha$ and $\beta$, the sure-almost-sure problem for a threshold Boolean objective $\varphi$ in a Markov decision process (MDP) asks if one can simultaneously ensure that all outcomes of the MDP have $\varphi$-value at least $\alpha$ (i.e. sure $\alpha$ satisfaction) and with probability $1$ the outcome has $\varphi$-value at least $\beta$ (i.e. almost-sure $\beta$ satisfaction). The sure-limit-sure problem asks if for all $\varepsilon > 0$ one can simultaneously ensure that all outcomes have $\varphi$-value at least $\alpha$ and with probability at least $1 - \varepsilon$ the outcome has $\varphi$-value at least $\beta$. Moreover, if simultaneous satisfaction of objectives is possible, then one would also like to construct a strategy (for sure-almost-sure) or a family of strategies (for sure-limit-sure) that achieves this. In this paper, we solve the sure-almost-sure and sure-limit-sure problems for window mean-payoff objectives. The window mean-payoff objective strengthens the standard mean-payoff objective by requiring that eventually, from every point in the infinite run, the average payoff becomes greater than a given threshold within a finite window length. We study two variants of window mean payoff: in the fixed variant, the window length $\ell$ is given, while in the bounded variant, the length is not given but is required to be bounded throughout the run. We show that the sure-almost-sure problem and the sure-limit-sure problem are both in P for the fixed variant (if $\ell$ is given in unary) and are both in NP $\cap$ coNP for the bounded variant, matching the computational complexity of sure satisfaction and almost-sure satisfaction when considered separately for these objectives. We also give bounds for the memory requirement of winning strategies for all considered problems.

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21.
medRxiv (Medicine) 2026-06-22

Symptom-based phenotype discovery in motor neuron disease using natural language processing of electronic health records

Authors:
Abdulle↗Dinu↗Wu↗Kim↗Budhdeo↗Yao↗Tomlinson↗Al-Chalabi↗Dobson↗Iacoangeli↗

Background: Motor neuron disease (MND) is a fatal neurodegenerative condition with significant clinical heterogeneity that is incompletely captured by existing phenotype classifications based on onset site. Electronic health records (EHRs) contain detailed symptom documentation in clinical narratives that may enable data-driven discovery of clinically meaningful patient subgroups. Methods: We developed a natural language processing (NLP) pipeline using MedCAT to extract symptoms from clinical notes of 2,361 people with a confirmed diagnosis of MND at a tertiary neurology center. MND cohort confirmation used three complementary methods: clinic attendance records, text-based diagnosis detection, and NLP extraction with negation detection. Extracted symptoms were filtered to Unified Medical Language System semantic type T184 (Sign or Symptom) with removal of negated concepts. Patients were clustered using latent class analysis on binary symptom profiles. Survival differences were assessed using Kaplan-Meier analysis, log-rank tests, and Cox proportional hazards regression. Results: From the first clinical notes, we identified four clusters of symptoms among 872 patients and 76 symptoms: Motor-Bulbar (n=373), Motor-Tremor (n=154), Sensory-Pain (n=222), and Motor-Respiratory (n=123). When extended to all clinical notes (n=2,065; 184 symptoms), these reorganized into three clusters: Autonomic-Respiratory (n=472), Nocturnal-Respiratory (n=338), and Classic Motor (n=1,255). Survival differences were significant across all clusters in both the first notes and all notes analyses (log-rank p < 0.001). Conclusions: NLP-based symptom extraction from EHRs identifies clinically meaningful MND subgroups that extend beyond traditional onset-site classifications. Autonomic-respiratory symptom burden is associated with poorer survival while a newly identified Sensory-Pain subtype with a better prognosis. These data-driven phenotypes may improve prognostication and inform targeted supportive care.

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22.
arXiv (CS.CL) 2026-06-19

A Survey of On-Policy Distillation for Large Language Models

Authors:
Mingyang Song↗Mao Zheng↗

As Large Language Models continue to grow in both capability and cost, transferring frontier capabilities into smaller, deployable students has become an important engineering problem, and knowledge distillation remains a common technique for this transfer. The prevailing recipe in industrial pipelines, static imitation of teacher-generated text, carries a structural weakness that grows more severe as tasks become longer and more reasoning-intensive. Because the student is trained on flawless teacher prefixes but generates its own at inference, small errors tend to accumulate into trajectories it has rarely been trained to recover from, and the resulting exposure bias has been shown to scale roughly with the square of sequence length. On-Policy Distillation reorganizes the training loop around this observation by having the teacher provide feedback on what the student actually produces, with the goal of reducing the compounding term toward linear and reframing distillation as an iterative correction process rather than single-pass imitation. The resulting literature has expanded along divergence design, reward-guided optimization, and self-play, yet contributions remain scattered across the knowledge distillation, RLHF, and imitation learning communities without a unified treatment. This survey provides such a treatment. We formalize OPD as f-divergence minimization over student-sampled trajectories, organize the field along three design axes (what to optimize, where the signal comes from, and how to stabilize training in practice), and consolidate success conditions, recurring failure modes, and the connection between OPD and KL-constrained reinforcement learning. We close with open problems that emerge from this synthesis, including distillation scaling laws, uncertainty-aware feedback, agent-level distillation, and the growing overlap between knowledge distillation and RL.

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23.
Nature Medicine 2026-06-09

Adjuvanted inactivated rabies virus-vectored Lassa virus vaccine in healthy adults: a phase 1 trial

Authors:
Justin R. Ortiz↗

Lassa fever causes substantial morbidity and mortality in West Africa, and no licensed vaccine is available. We evaluated LASSARAB, an inactivated rabies virus-vectored Lassa virus (Josiah strain) glycoprotein complex vaccine. We conducted a randomized, controlled, dose-escalation phase 1 trial. Participants (total n = 54) received two intramuscular doses of LASSARAB containing 700 (n = 15), 1,400 (n = 15) or 2,800 (n = 14) relative units of antigen formulated with the TLR-4 agonist 3D-6-acyl PHAD-SE adjuvant, or licensed rabies vaccine control (n = 10), administered 28 days apart. This protocol-defined interim analysis reports the primary safety evaluation and secondary immunogenicity assessments through day 61. There were no prespecified hypotheses or formal power calculations. All primary safety end points demonstrated an acceptable safety profile. After dose 1, local solicited adverse events occurred in 86.7–100.0% of LASSARAB groups and 80% of controls; systemic events in 33.3–71.4% and 60.0% of controls. After dose 2, local solicited adverse events occurred in 66.7–86.7% of LASSARAB groups and 55.6% of controls; systemic events in 53.3–71.4% of LASSARAB groups and 55.6% of controls. Events were predominantly mild and self-limited. Unsolicited adverse events occurred in 28.6–60.0% of LASSARAB groups and 20.0% of controls. No serious adverse event, immune-mediated condition or sensorineural hearing loss occurred. Safety laboratory abnormalities occurred in 13.3–66.7% of LASSARAB groups and 30.0% of controls (14 mild, 6 moderate and none severe). After two doses, Lassa virus GPC IgG ELISA seroconversion (≥fourfold rise) was achieved in 100.0% (44 of 44) of LASSARAB recipients and 0.0% (0 of 10) of controls. Rabies glycoprotein IgG ELISA seroconversion (≥fourfold rise) and neutralizing antibody by rapid fluorescent focus inhibition test (RFFIT) seroprotection (≥0.5 IU ml−1) were also 100% across all groups, including controls. LASSARAB + 3D-6-acyl phosphorylated hexaacyl disaccharide (PHAD)-SE demonstrated a favorable safety profile and immunogenicity against Lassa and rabies viruses. The per-protocol final study report will include safety and durability through day 394. ClinicalTrials.gov identifier NCT06546709 . An interim report of a first-in-human phase 1 trial found an adjuvanted, combination inactivated rabies-vectored, Lassa fever vaccine (LASSARAB + 3D-6-acyl PHAD-SE) to be safe and induced immunogenicity to both Lassa and rabies viruses in healthy participants.

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24.
arXiv (CS.LG) 2026-06-11

Adjoint Method versus Physics-Informed Neural Networks in PDE-Constrained Inverse Problems

Authors:
Zhen Zhang↗Alessandro Alla↗George Em Karniadakis↗

arXiv:2606.12337v1 Announce Type: cross Abstract: Inverse problems governed by partial differential equations (PDEs) are central to computational mechanics and are commonly solved by adjoint-based optimization, while physics-informed neural networks (PINNs) have emerged as a flexible alternative. Their relative performance remains difficult to assess because the two approaches are often compared under different formulations, parameterizations, optimizers, and regularization choices. We present a fair comparison of adjoint optimization and PINNs for PDE-constrained inverse problems. From a common abstract formulation, we instantiate both methods on identical domains, governing equations, observation models, and regularization terms, while matching the optimizer, unknown parameterization, and arithmetic precision wherever applicable. The benchmarks include unsteady Burgers, noisy Darcy permeability inversion, three-dimensional Allen–Cahn reaction identification, and unsteady Navier–Stokes viscosity identification. The results show that the representation of the unknown largely determines the preferred method: grid-based fields favor the discrete adjoint, whereas neural representations are native to PINNs and relevant for closure and constitutive modeling. For time-dependent problems, adjoint inversion can be dominated by trajectory storage and differentiation, while PINNs provide satisfactory reconstructions at lower cost. A PINN-warm-started adjoint strategy then recovers adjoint-level accuracy at substantially reduced cost.

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

Attention-Based Estimation of the Individual Treatment Benefit Probability under Dose Variation

Authors:
Lev V. Utkin↗Andrei V. Konstantinov↗Stanislav K. Kogan↗Natalya M. Verbova↗Maksim I. Goriunov↗

arXiv:2606.13821v1 Announce Type: new Abstract: Estimating the probability that a treatment outperforms a control for an individual patient, called the Individual Probability of Treatment Benefit (IPTB), offers a clinically intuitive alternative to population-average metrics. However, existing methods for IPTB estimation are largely confined to binary treatment settings, despite the prevalence of dose-varying interventions in clinical practice. We propose a general framework for IPTB estimation with ordinal outcomes under discrete dose assignments, called Dose-AIPTB (Dose Attention-based IPTB). Our approach recasts the problem as binary classification over the unobserved sign of the individual treatment effect, constructing pseudo-labels from covariate-similar pairwise comparisons and aggregating them via attention mechanisms or Nadaraya-Watson kernel regression. This formulation naturally accommodates multiple discrete dose levels, extending beyond the binary treatment paradigm. Through numerical experiments on real-world and synthetic data under covariate shift, varying sample sizes, and heterogeneous outcomes, we demonstrate that attention-based aggregation consistently outperforms kernel alternatives. The framework provides a foundation for personalized dose selection grounded in individual-level benefit probabilities. Codes implementing the model are publicly available at https://github.com/NTAILab/AIPTBDose.

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