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

What Must Generalist Agents Remember?

arXiv:2606.18746v1 Announce Type: new Abstract: This paper develops a formal account of what generalist agents must store in memory in order to act near-optimally across multiple environments and goals. It shows that when two domains share an observational bottleneck but require incompatible optimal actions, any uniformly near-optimal policy must induce distinct memory distributions at that bottleneck. The result yields a separation theorem: sufficiently successful agents cannot rely only on current state observations, but must preserve domain-relevant information in memory. The paper further shows that if an agent's memory contains enough information to estimate values for related goals, then that memory can be used to approximately reconstruct the agent's local transition dynamics. Together, these results characterize memory as the substrate that supports domain disambiguation, transition-model reconstruction, and planning for generalist agents.

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

Stop the Sampler! Classifier-Based Adaptive Stopping for Sampling Kernels

arXiv:2606.16073v1 Announce Type: new Abstract: Sampling from complex, unnormalized probability densities is a fundamental challenge in Bayesian inference and probabilistic modeling. While Markov chain Monte Carlo (MCMC) methods provide asymptotic guarantees, they often suffer from slow mixing and high computational costs due to fixed or manually tuned trajectory lengths. In this work, we propose a novel framework that treats trajectory termination as a learnable component of the sampling dynamics. By framing MCMC within the theory of non-acyclic generative flow networks (GFlowNets), we train state-dependent neural classifiers to decide when a trajectory has reached a high-density region and should terminate. We theoretically establish the connection between optimal classifiers and the target density via detailed balance conditions and introduce a multilevel training scheme to facilitate exploration in complex geometries. Experimental results across various benchmark densities demonstrate that our approach significantly reduces average trajectory lengths while improving mode coverage and mixing compared to standard MCMC baselines.

03.
arXiv (CS.LG) 2026-06-17

Beyond Independent Genes: Learning Module-Inductive Representations for Single-Cell Gene Perturbation Prediction

arXiv:2602.04901v2 Announce Type: replace-cross Abstract: Predicting transcriptional responses to genetic perturbations is a central problem in functional genomics. In practice, perturbation responses are rarely gene-independent but instead manifest as coordinated, program-level transcriptional changes among functionally related genes. However, most existing methods do not explicitly model such coordination, due to gene-wise modeling paradigms and reliance on static biological priors that cannot capture dynamic program reorganization. To address these limitations, we propose scBIG, a module-inductive perturbation prediction framework that explicitly models coordinated gene programs. scBIG induces coherent gene programs from data via Gene-Relation Clustering, captures inter-program interactions through a Gene-Cluster-Aware Encoder, and preserves modular coordination using structure-aware alignment objectives. These structured representations are then modeled using conditional flow matching to enable flexible and generalizable perturbation prediction. Extensive experiments on multiple single-cell perturbation benchmarks show that scBIG consistently outperforms state-of-the-art methods, particularly on unseen and combinatorial perturbation settings, achieving an average improvement of 6.7% over the strongest baselines. The code is available at https://github.com/ttruan2426-dot/scBIG.

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

A Unified Perspective on the Dynamics of Deep Transformers

arXiv:2501.18322v2 Announce Type: replace Abstract: Transformers, which are state-of-the-art in most machine learning tasks, represent the data as sequences of vectors called tokens. This representation is then exploited by the attention function, which learns dependencies between tokens and is key to the success of Transformers. However, the iterative application of attention across layers induces complex dynamics that remain to be fully understood. To analyze these dynamics, we identify each input sequence with a probability measure and model its evolution as a Vlasov equation called Transformer PDE, whose velocity field is non-linear in the probability measure. Our first set of contributions focuses on compactly supported initial data. We show the Transformer PDE is well-posed and is the mean-field limit of an interacting particle system, thus generalizing and extending previous analysis to several variants of self-attention: multi-head attention, L2 attention, Sinkhorn attention, Sigmoid attention, and masked attention–leveraging a conditional Wasserstein framework. In a second set of contributions, we are the first to study non-compactly supported initial conditions, by focusing on Gaussian initial data. Again for different types of attention, we show that the Transformer PDE preserves the space of Gaussian measures, which allows us to analyze the Gaussian case theoretically and numerically to identify typical behaviors. This Gaussian analysis captures the evolution of data anisotropy through a deep Transformer. In particular, we highlight a clustering phenomenon that parallels previous results in the non-normalized discrete case.

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

Benchmark of quantum algorithms for ground state preparation in the presence of noise

arXiv:2606.20551v1 Announce Type: new Abstract: We compare the performance of representative cooling, adiabatic, and optimization algorithms for ground-state preparation in the presence of noise. Using an exactly solvable family of quadratic fermionic Hamiltonians subject to depolarizing noise, we derive the scaling of the achievable relative energy as a function of the noise rate and support these results with numerical simulations. The Hamiltonian exhibits two phases, separated by a quantum phase transition. As expected, the performance of the different algorithms depends on the phase: adiabatic evolution is favorable in the trivial phase, while a multi-frequency cooling algorithm, as proposed in [1], becomes competitive or superior in the topological phase, where gap-closing limits adiabatic protocols. We further present numerical results for the quantum approximate optimization algorithm [2], showing that it performs competitively with cooling in the trivial phase but is typically outperformed in the topological regime. Finally, we show that for this model the cooling protocol exhibits enhanced robustness to parameter imperfections, highlighting its potential advantage for realistic implementations of noisy quantum state preparation. The analytical approach developed here, in conjunction with numerical validation, establishes an extendable approach to benchmarking ground-state preparation algorithms.

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

Symmetry and Topology of Monitored Quantum Dynamics

arXiv:2412.06133v4 Announce Type: replace-cross Abstract: The interplay between unitary dynamics and quantum measurements induces diverse phenomena in open quantum systems with no counterparts in closed quantum systems at equilibrium. Here, we generally classify Kraus operators and their effective non-Hermitian dynamical generators, thereby establishing the tenfold classification for symmetry and topology of monitored free fermions. Our classification elucidates the role of topology in measurement-induced phase transitions and identifies potential topological terms in the corresponding nonlinear sigma models. Furthermore, we establish the bulk-boundary correspondence in monitored quantum dynamics: nontrivial topology in spacetime manifests itself as topologically nontrivial steady states and gapless boundary states in Lyapunov spectra, such as Lyapunov zero modes and chiral edge modes, leading to the topologically protected slowdown of dynamical purification.

07.
arXiv (quant-ph) 2026-06-16

A complexity theory for non-local quantum computation

arXiv:2505.23893v2 Announce Type: replace Abstract: Non-local quantum computation (NLQC) replaces a local interaction between two systems with a single round of communication and shared entanglement. Despite many partial results, it is known that a characterization of entanglement cost in at least certain NLQC tasks would imply significant breakthroughs in complexity theory. Here, we avoid these obstructions and take an indirect approach to understanding resource requirements in NLQC, which mimics the approach used by complexity theorists: we study the relative hardness of different NLQC tasks by identifying resource efficient reductions between them. Most significantly, we prove that $f$-measure and $f$-route, the two best studied NLQC tasks, are in fact equivalent under $O(1)$ overhead reductions. This result simplifies many existing proofs in the literature and extends several new properties to $f$-measure. For instance, we obtain sub-exponential upper bounds on $f$-measure for all functions, and efficient protocols for functions in the complexity class $\mathsf{Mod}_k\mathsf{L}$. Beyond this, we study a number of other examples of NLQC tasks and their relationships.

08.
medRxiv (Medicine) 2026-06-11

Dissecting the functional landscape of rare diseases through genomic variation in a heterogeneous cohort of 11,000 patients

Rare diseases (RDs) remain a major diagnostic challenge. Genetic and phenotypic heterogeneity, incomplete knowledge of disease mechanisms, and limitations in variant clinical interpretation leave many patients without a molecular diagnosis. Meanwhile, the growing volume of genomic data generated in clinical practice offers an opportunity to develop data-driven methodologies for exploring disease mechanisms and improving the reanalysis of unsolved cases. We aggregated real-world genomic data from 11,084 unrelated patients with suspected RD. Patients were clinically classified into 122 diseases. We built a multi-disease genomic variant frequency database (FJD-DB), which enabled the development of variant and gene-disease association scores by means of case-control subcohort comparisons across 32 disease groups. Functional enrichment analyses were then used to highlight disease-associated protein domains, pathways, biological processes, and phenotypes. Finally, the resulting knowledge was integrated into a data-driven framework for the guided reanalysis of unsolved RD patients applied to Inherited Retinal Dystrophies (IRD) patients as first use case. FJD-DB contained more than 45 million unique variants, including ~185,000 potentially pathogenic variants. Disease-specific analyses identified disease-associated pathogenic variants and highlighted both established and candidate disease genes. We detected 179 significantly enriched protein domains across 23 diseases, 124 Human Phenotype Ontology terms across 13 diseases, 79 Reactome pathways across 10 diseases, and 72 Gene Ontology biological processes across 8 diseases, revealing highly disease-specific functional signatures. Integration of disease-specific variant, gene, and functional association signals enabled the development of a data-driven framework for guided reanalysis of unsolved RD cases. Applied to more than 1,100 unsolved IRD cases, the framework generated clinically relevant findings in 26 patients, including four molecular diagnoses, seven candidate diagnoses, and 15 cases upgraded from non-informative findings to variants of uncertain significance. Aggregated real-world genomic data can be leveraged to identify disease-associated molecular signals generating novel biological hypotheses. A unified analytical framework provides a scalable strategy for knowledge discovery and guided reanalysis, facilitating the identification of overlooked and potentially novel genetic causes of RDs.

09.
bioRxiv (Bioinfo) 2026-06-20

Seed variation impacts clustering stability in Single-Cell RNA-Seq and can be mitigated by StAbility-BasEd-Reassignment (SABER)

Single-cell RNA-seq clustering is commonly treated as reproducible once a random seed is fixed, yet the choice of seed itself may alter cell assignments and downstream interpretation. We systematically quantified seed-induced clustering variability by running Louvain and Leiden clustering across 100 seeds in Seurat and Scanpy on 28 single-cell RNA-seq datasets from the Human Cell Atlas and IMMUcan. Using Element-Centric Consistency, we found that seed choice affected a substantial fraction of cells, with Scanpy showing more unstable assignments than Seurat on average, 40.46% versus 26.78% unstable cells, respectively. This increased stability came at a marked computational cost: Seurat required approximately 19-fold higher median memory than Scanpy. Seed-dependent clustering variability also propagated to cell-type annotation, particularly among transcriptionally related populations including macrophage/monocyte, endothelial/epithelial and T/NK cell states. To mitigate this instability, we developed StAbility-BasEd Reassignment (SABER), a Scanpy-based framework that identifies seed-sensitive cells across repeated clusterings and reassigns them to stable cluster cores using cosine similarity. SABER improved clustering quality while preserving annotation concordance and reduced median memory usage 3.5-fold compared with Seurat-Louvain. Our results identify seed choice as an underappreciated source of variability in single-cell analysis and provide a scalable strategy to improve clustering robustness.

10.
Nature Medicine 2026-06-22

Biological aging and generational shifts in early-onset cancer risk

Authors:

Incidence of early-onset cancer is rising globally in recent generations, which underscores the need to elucidate the influence of emerging generational risk factors. Systemic and organ-specific aging reflects the cumulative impact of exposures and may provide an integrative and complementary approach to understand early-onset cancer risk. Here among 154,169 young adults from the United Kingdom Biobank, systemic aging measured by PhenoAge increased across birth cohorts, with 23% s.d. increase for those born 1965–1974 versus 1950–1954, and was associated with early-onset solid cancer risk (hazard ratio (HR)per s.d. 1.08; 95% confidence interval (CI), 1.03–1.13), driven by lung, gastrointestinal and uterine cancers, independent of genetic risks of aging and cancer. Patterns were consistent using alternative systemic aging measures, including the Klemera–Doubal method-defined age gap and metabolomic-based age gap. These findings were validated partially among 10,262 participants in the United States All of Us Research Program. Proteomics-based organ-specific aging analyses linked immune aging with early-onset lung cancer (HRper s.d. 1.89; CI, 1.20–2.97) and adipose tissue aging to early-onset colorectal cancer (HR 1.60; CI, 1.11–2.32). Greater age gap, reflecting more advanced biological aging relative to chronological age, may serve as a driver associated with risk of early-onset solid cancers, highlighting the importance of uncovering underlying mechanisms to guide effective prevention strategies. Analyses of population cohorts found that young adults exhibited earlier systemic and organ-specific aging, which was associated with increased risk of early-onset cancer compared with older adults born decades earlier.

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

Single Photon Cross-Phase Shifts Can Be Enhanced by Localization in both Frequency and Time

arXiv:2606.11516v1 Announce Type: new Abstract: Single-photon optical nonlinearities face a fundamental trade-off: maximum nonlinearity requires both spectral resonance (narrow bandwidth) and high peak intensity (short duration), constraints that are incompatible due to the time-energy uncertainty relation. We demonstrate experimentally that this limitation does not need to exist in cases involving post-selection. We measure a cross-phase shift (XPS) produced by a resonant photon from a narrow-band source that is first transmitted through a cold atomic cloud and then localized in time through detection. The peak size of this XPS is greatly enhanced compared to that of Gaussian single-photon-level pulses without post-selection, benefiting from the narrow bandwidth of the resonant prepared state and the high intensity of the post-selected state simultaneously. We measure enhancements in the peak XPS of 6$\pm$1 at an optical depth (OD) of 2.4$\pm$0.1, and our results are in qualitative agreement across a range of optical depths with the recently developed weak value theory of atomic excitation [Thompson et al., APL Quantum 2, 036108 (2025)] for such post-selected photons. This work uncovers new consequences of having simultaneous knowledge of frequency and time, raising new foundational questions about how a particle behaves, and interacts with other systems, when its preparation and post-selection are non-commuting.

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

Dynamic Symmetric Point Tracking: Tackling Non-ideal Reference in Analog In-memory Training

arXiv:2602.21321v2 Announce Type: replace Abstract: Analog in-memory computing (AIMC) performs computation directly within resistive crossbar arrays, offering an energy-efficient platform to scale large vision and language models. However, non-ideal analog device properties make the training on AIMC devices challenging. In particular, its update asymmetry can induce a systematic drift of weight updates towards a device-specific symmetric point (SP), which typically does not align with the optimum of the training objective. To mitigate this bias, most existing works assume the SP is known and pre-calibrate it to zero before training by setting the reference point as the SP. Nevertheless, calibrating AIMC devices requires costly pulse updates, and residual calibration error can directly degrade training performance. In this work, we present the first theoretical characterization of the pulse complexity of SP calibration and the resulting estimation error. We further propose a dynamic SP estimation method that tracks the SP during model training, and establishes its convergence guarantees. In addition, we develop an enhanced variant based on chopping and filtering techniques from digital signal processing. Numerical experiments demonstrate both the efficiency and effectiveness of the proposed method.

13.
arXiv (CS.AI) 2026-06-11

HERO: Hindsight-Enhanced Reflection from Environment Observations for Agentic Self-Distillation

arXiv:2606.11559v1 Announce Type: new Abstract: Reinforcement learning typically improves multi-turn agent capabilities through the terminal outcome of the trajectories, which makes it difficult to determine credit assignments for each intermediate turns. Recent on-policy self-distillation methods offer a promising alternative by converting privileged feedback into dense token-level supervision through a self-teacher. Our study is motivated by the unexpected performance degradation observed when naively extending this paradigm to multi-turn settings, which we attribute to a lack of alignment between privileged feedback, such as successful trajectories or terminal outcomes, and the student's current decision context. We introduce HERO, a hindsight-enhanced self-distillation framework that uses next environment observations as locally aligned feedback. After each rollout, HERO reflects on the completed interaction to convert each observation into a compact turn-level diagnosis, that captures actionable feedback about the original action such as its necessity, validity or failure cause. On TauBench and WebShop, HERO improves task success and reduces unnecessary turns over environment-feedback-only self-distillation and GRPO. It is especially effective under limited training turn budgets, where successful rollouts are rare and GRPO provides weak reward-contrast signals.

14.
arXiv (CS.LG) 2026-06-19

Pose6DAug: Physically Plausible Multi-view Object Swapping for Robot Data Augmentation

arXiv:2606.20118v1 Announce Type: cross Abstract: Vision-language-action (VLA) policies have shown strong potential for general-purpose manipulation, yet they often fail on novel, out-of-distribution objects whose appearance or geometry deviates from the training distribution. The standard remedy is to collect multi-view teleoperation data for every failure case, but this scales poorly in both cost and time. We introduce Pose6DAug, a failure-driven data augmentation framework that turns a policy's own successful episodes into targeted demonstrations for its failure modes, without any new data collection. Our key insight is that each successful episode already encodes a physically valid action trajectory together with calibrated multi-view observations. By swapping only the manipulated object while preserving this trajectory, we obtain new and physically grounded demonstrations. However, naive 2D video editing breaks multi-view consistency and physical plausibility, particularly under heavy occlusion and egocentric viewpoints. Our method instead operates directly in 3D, anchoring the target object with an explicit mesh driven by a temporally coherent 6D pose trajectory, ensuring geometrically consistent renderings across all camera views. Fine-tuning a VLA on data augmented by our method improves success rates by 16.5% relative to the state-of-the-art baseline on novel objects, while preserving in-distribution performance. These results show that multi-view and physically consistent augmentation is a practical path to scalable VLA generalization.

15.
arXiv (CS.CL) 2026-06-12

MaxProof: Scaling Mathematical Proof with Generative-Verifier RL and Population-Level Test-Time Scaling

We present MaxProof, a population-level test-time scaling framework for competition-level mathematical proof in the MiniMax-M3 series. M3 first trains three proof-oriented capabilities – proof generation, proof verification, and critique-conditioned proof repair – using a defense-in-depth generative verifier engineered for low false-positive rate. These capabilities are merged into a single released M3 model. At test time, MaxProof treats the model as a generator, verifier, refiner, and ranker, searches over a population of candidate proofs, and returns one final proof through tournament selection. With MaxProof test-time scaling, the M3 model reaches 35/42 on IMO 2025 and 36/42 on USAMO 2026, exceeding the human gold-medal threshold on both.

16.
arXiv (CS.CL) 2026-06-12

On Sequence-to-Sequence Models for Automated Log Parsing

Context: Log parsing is a critical standard operating procedure in software systems, enabling monitoring, anomaly detection, and failure diagnosis. However, automated log parsing remains challenging due to heterogeneous log formats, distribution shifts between training and deployment data, and the brittleness of rule-based approaches. Objectives: This study aims to systematically evaluate how sequence modelling architecture, representation choice, sequence length, and training data availability influence automated log parsing performance and computational cost. Methods: We conduct a controlled empirical study comparing four sequence modelling architectures: Transformer, Mamba state-space, monodirectional LSTM, and bidirectional LSTM models. In total, 396 models are trained across multiple dataset configurations and evaluated using relative Levenshtein edit distance with statistical significance testing. Results: Transformer achieves the lowest mean relative edit distance (0.111), followed by Mamba (0.145), mono-LSTM (0.186), and bi-LSTM (0.265), where lower values are better. Mamba provides competitive accuracy with substantially lower computational cost. Character-level tokenization generally improves performance, sequence length has negligible practical impact on Transformer accuracy, and both Mamba and Transformer demonstrate stronger sample efficiency than recurrent models. Conclusion: Overall, Transformers reduce parsing error by 23.4%, while Mamba is a strong alternative under data or compute constraints. These results also clarify the roles of representation choice, sequence length, and sample efficiency, providing practical guidance for researchers and practitioners.

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

ConSA: Controllable Sparsity in Hybrid Attention via Learnable Allocation

Hybrid architectures combining full attention (FA) and sliding-window attention (SWA) are a promising paradigm for efficient LLM inference. However, existing methods typically rely on hand-crafted rules or simple post-hoc heuristics for FA/SWA allocation and offer limited analysis of the attention behaviors underlying these designs. We propose Controllable Sparsity in Hybrid Attention (ConSA), a framework that learns optimal FA/SWA assignment under a user-specified sparsity target. ConSA employs L0 regularization to learn binary masks selecting between FA and SWA for each attention unit, while an augmented Lagrangian constraint enforces the target sparsity at either layer or KV-head granularity. We evaluate ConSA on two LLMs at the 0.6B and 1.7B scales. Learned allocations consistently outperform rule-based baselines, with KV-head-wise allocation yielding clear gains over layer-wise allocation. The learned patterns place SWA in the bottom layers and concentrate FA into contiguous middle-layer blocks, diverging from evenly interleaved patterns in rule-based methods. This structure persists across model scales, sparsity levels, and allocation granularities, revealing a fine-grained spectrum of intrinsic attention behaviors that underlies the learned allocation.

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

ScaffoldAgent: Utility-Guided Dynamic Outline Optimization for Open-Ended Deep Research

arXiv:2606.20122v1 Announce Type: new Abstract: Open-ended deep research (OEDR) requires systems to acquire knowledge through multi-round retrieval and generate coherent long-form reports. The outline plays a central role as a structural scaffold that coordinates retrieval, evidence organization, and generation. However, existing methods either fix the outline before writing or refine it with local heuristics, leading to scaffold drift under continuous information accumulation and delayed feedback for evaluating outline modifications. We propose ScaffoldAgent, a utility-guided dynamic outline optimization framework for OEDR. ScaffoldAgent models outline evolution as a structured decision process with three operations: Expansion, Contraction, and Revision, enabling controlled updates to the report scaffold. It further introduces a utility-guided feedback mechanism that estimates the downstream value of each outline operation from retrieval gain, structural coherence, and trial-generation quality. The resulting utility signal guides node selection, operation scheduling, and termination during inference. Experiments on DeepResearch Bench and DeepResearch Gym show that ScaffoldAgent consistently improves long-form report generation and factual grounding over existing deep research agents.

19.
arXiv (CS.AI) 2026-06-17

A homotopy-type-theoretic generalization of neurosymbolic inference

arXiv:2606.17851v1 Announce Type: new Abstract: A wide range of neurosymbolic (NeSy) systems compute one functional: a belief-weighted sum of a logical quantity over a space of $\sigma$-structures, of which weighted model counting, fuzzy logic, and probabilistic logic are special cases. This account is built on sets, and a set deliberately forgets two things that are important for NeSy: when two $\sigma$-structures are the same up to a symmetry of the theory, and how many distinct proofs witness a query. Replacing the underlying sets by types, in the sense of homotopy type theory, preserves this information, and turns this functional into a belief-weighted homotopy cardinality, a notion of size that counts each object in inverse proportion to its symmetries. We develop the framework from scratch for NeSy systems, prove a conservativity theorem that recovers the classical functional when symmetries are trivial, and show that the symmetry our framework exposes is exactly the one behind reasoning shortcuts. The payoff is concrete: the shortcut-aware concept posterior that recent methods reach by ensembling or expressive density estimation is the only symmetry-invariant point of the confusion-set simplex, computable in closed form by averaging a single model over the symmetry group. On MNIST reasoning-shortcut benchmarks this single-model wrapper is better calibrated than a diversity-trained ensemble, while leaving label accuracy and identifiable concepts untouched. Code is freely available at https://github.com/bio-ontology-research-group/hott-nesy.

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

Harsher on Male? Evaluating LLMs on Gender-Asymmetric Moral Framing Across Diverse Conflict Scenarios

Existing studies on gender bias in LLMs have largely focused on stereotypes, occupational associations, or explicit harmful outputs. In this work, we ask whether LLMs apply consistent response standards to the same negative behavior under matched male-actor and female-actor conditions. We introduce GAMA-Bench, a gender-mirrored benchmark of 1,298 scenarios covering intimate relationship and public social conflicts. It constructs gender-neutral misconduct templates through controlled grids and cross-model review, then compiles them into paired first-person prompts with matched actor-gender and role-reference variations. We further design a structured response-framing protocol to measure how models allocate punishment, empathy, escalation, instruction, and blame. Experiments on 10 representative LLMs reveal a consistent male-disadvantaging asymmetry: male actors receive more punitive, escalatory, and blame-centered framing, whereas female actors receive more therapeutic and empathy-oriented framing for the same misconduct. Further analyses show that this pattern persists across model families, scenario tracks, model scale, and explicit thinking-style reasoning. The official code is available at https://github.com/xufeiqiong/GAMA-Bench.

21.
arXiv (CS.LG) 2026-06-15

Muon$^p$: Muon with Fractional Spectral Powers

arXiv:2606.13867v1 Announce Type: new Abstract: Muon is an increasingly widely used optimizer that replaces a gradient $G=USV^\top$ with its polar factor $UV^\top$, thereby flattening the singular spectrum. However, full flattening discards singular-value information that may matter for adaptation. We introduce Muon$^p$, a Muon-style optimizer that instead uses fractional spectral-power updates $US^pV^\top$ for rational $p\in(0,1)$, interpolating between Muon and gradient descent. To make it practical, we prove that fractional spectral powers cannot be computed by any fixed univariate polynomial iteration, and furthermore derive low-degree odd bivariate recurrences that approximate $US^pV^\top$ using only matrix multiplications, preserving Muon's matrix-multiplication-only structure and compute complexity. We show that Muon$^p$ maximizes the linear improvement in loss under the Schatten $q$-norm for $q=1+\frac{1}{p}$. Empirically, Muon$^p$ is especially effective for finetuning: on billion-scale models, Muon$^p$ improves validation perplexity and downstream task performance. We further analyze when Muon$^p$ is less suitable, through the lens of spectral geometry. Our results reveal important insights on when preserving the singular spectrum can bring significant gains, and introduce a principled way to achieve them.

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

The Hidden Cost of Approximation in Online Mirror Descent

arXiv:2511.22283v2 Announce Type: replace Abstract: Online mirror descent (OMD) is a fundamental algorithmic paradigm that underlies many algorithms in optimization, machine learning and sequential decision-making. The OMD iterates are defined as solutions to optimization subproblems which, oftentimes, can be solved only approximately, leading to an inexact version of the algorithm. Nonetheless, existing OMD analyses typically assume an idealized error free setting, thereby limiting our understanding of performance guarantees that should be expected in practice. In this work we initiate a systematic study into inexact OMD, and uncover an intricate relation between regularizer smoothness and robustness to approximation errors. When the regularizer is uniformly smooth, we establish a tight bound on the excess regret due to errors. Then, for barrier regularizers over the simplex and its subsets, we identify a sharp separation: negative entropy requires exponentially small errors to avoid linear regret, whereas log-barrier and Tsallis regularizers remain robust even when the errors are only polynomial. Finally, we show that when the losses are stochastic and the domain is the simplex, negative entropy regains robustness-but this property does not extend to all subsets, where exponentially small errors are again necessary to avoid suboptimal regret.

23.
Nature (Science) 2026-06-10

A first-in-class pulsatile FXR agonist for bile-acid-related liver diseases

Authors:

Nuclear receptors are central regulators of metabolism1, yet therapeutic strategies that enforce continuous receptor activation frequently lead to reduced efficacy and unacceptable toxicity. Here we report a first-principles drug design strategy that aligns pharmacokinetics with physiological signalling cycles. We developed linafexor, a potent non-bile-acid agonist of the farnesoid X receptor (FXR)2; it is engineered for rapid systemic clearance, which enables pulsatile receptor activation that mirrors endogenous bile acid dynamics3–5. Linafexor has robust efficacy across multiple preclinical models of metabolic dysfunction-associated steatohepatitis6, liver fibrosis7, primary biliary cholangitis and primary sclerosing cholangitis8,9. Transcriptomic analyses reveal that, unlike long-acting FXR agonists10,11, linafexor preserves cyclic FXR signalling, avoids receptor downregulation and prevents broad transcriptional dysregulation. Direct manipulation of delivery patterns demonstrates that sustained FXR activation—independent of compound identity—induces severe toxicity, establishing activation duration as a determinant of therapeutic index. In phase 1 clinical studies (ClinicalTrials.gov; NCT05082779), linafexor administered once daily produces transient FXR pathway engagement, marked by (1) induction of FGF1912–14, a key endocrine mediator of bile acid feedback regulation; and (2) suppression of C415, an intermediate reflecting hepatic bile acid synthesis, with no treatment-related adverse events. Together, these findings identify pulsatile FXR activation as a mechanistically grounded and clinically translatable strategy, and establish linafexor as a first-in-class therapeutic for bile acid–related liver diseases. Linafexor is a rapidly cleared FXR agonist designed to mimic natural bile acid signalling, achieving transient receptor activation with strong efficacy and reduced toxicity in preclinical and early clinical studies.

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

FlowEdit: Associative Memory for Lifelong Pronunciation Adaptation in Flow-Matching TTS

arXiv:2606.20518v1 Announce Type: new Abstract: Flow-matching text-to-speech systems achieve remarkable zero-shot quality but remain static after deployment: pronunciation errors on out-of-vocabulary proper nouns persist unless the model is retrained. We introduce FlowEdit, a life-long adaptation framework for frozen flow-matching TTS that learns pronunciation corrections as latent conditioning edits rather than weight updates. When corrective feedback is provided, FlowEdit optimizes a token-level perturbation in the text embedding space, then stores the correction in a Modern Hopfield Network serving as content-addressable episodic memory. At inference, corrections are retrieved via soft attention with a similarity gate, enabling fuzzy morphological matching. On our curated benchmark of 312 multilingual proper nouns across 18 language families, FlowEdit reduces target-word Phoneme Error Rate by 92.7% relative to the zero-shot baseline while maintaining identical general-speech quality. Corrections complete in approximately 15 seconds on a single GPU.

25.
medRxiv (Medicine) 2026-06-16

Reporting patterns of adverse drug withdrawal events using individual case safety reports in United States and European databases

Introduction: Adverse drug withdrawal events (ADWEs) are a key safety concern with deprescribing but are infrequently reported in trials. Although pharmacovigilance systems have advanced our understanding of medication-related harms, it is unclear how extensively these systems have been used for ADWEs. Objectives: To examine the reporting patterns of ADWEs for all drugs recorded in United States and European pharmacovigilance databases between 2004 and 2023. Methods: A retrospective study was conducted using two pharmacovigilance databases, the publicly available FDA-FAERS dataset and EMA-EV Level 2A (individual-level) dataset. ADWE cases were identified using relevant MedDRA preferred terms. Data on patient characteristics, reporter type, drugs, indication, ADWE outcomes, dechallenge/rechallenge, seriousness criteria, time to onset, duration, and causality were summarised. Results: A total of 158,505 ADWE reports were analysed (FDA-FAERS: 145,514; EMA-EV: 12,987), with mean ages of 46.1 (FDA; 55.3% female) and 45.5 years (EMA; 57.1% female). The frequently reported drug classes were opioids (FDA: oxycodone, 29.8%; EMA: buprenorphine, 19%), antidepressants (FDA: duloxetine, 32%; EMA: venlafaxine, 25.9%) and gabapentinoids (FDA: pregabalin, 6.7%; EMA: pregabalin, 6.0%). The most common adverse outcomes were other serious medical conditions (FDA=63.9%; EMA=46.0%), hospitalisation (FDA=15.9%; EMA=28.3%), and disability (FDA=13.3%; EMA=6.2%) and these outcomes varied significantly based on sex and age group (p