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01.
arXiv (CS.LG) 2026-06-17

Evaluating Open-Source LLMs for Multi-Label ATT&CK Technique Classification on CTI Reports

arXiv:2606.18166v1 Announce Type: cross Abstract: Classifying Cyber Threat Intelligence (CTI) using MITRE Adversarial Tactics, Techniques, and Common Knowledge (ATT&CK) is essential for proactive defense, but historically required extensive human effort. Pre-Large Language Model (LLM) automation sped up this process, but could not resolve the complex language and multi-step attack patterns found in unstructured CTI reports. LLMs addressed previous limitations by using contextual reasoning to understand unstructured text. However, current evaluations rely on simplified, single-technique sentences that ignore the complexity of real-world CTI reports, which often leads to inflated performance results. Consequently, the baseline performance of open-source LLMs on complex unstructured CTI reports remains unevaluated. To address this gap, we constructed a ground-truth dataset of 2,076 human-annotated sentences (1,281 technique-positive, 795 negative) from 83 complex unstructured CTI reports. These sentences were mapped to 114 unique ATT&CK techniques using a six-phase annotation process, achieving \k{appa} = 0.68 inter-annotator agreement. Using this dataset, we evaluated seven open-source LLMs ranging from 8B to 236B parameters across prompt strategy and temperature configurations. The highest-performing LLM achieved a micro-averaged F1 score of 0.22, establishing the empirical baseline for multi-label ATT&CK classification on complex unstructured CTI. Parameter size showed a statistically significant positive correlation with F1 score. Prompt strategy and temperature produced no statistically significant gains across model configurations. These results indicate that current open-source LLMs are insufficient for production-grade ATT&CK classification. The dataset, benchmark, and findings provide a reproducible foundation for future CTI research.

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

Kalman Linear Attention: Parallel Bayesian Filtering For Efficient Language Modelling and State Tracking

arXiv:2602.10743v2 Announce Type: replace Abstract: State-space language models such as Mamba and gated linear attention (GLA) offer linear-complexity, parallelisable alternatives to transformers, but their linear state updates limit expressivity and robust state tracking. We close this gap from a probabilistic angle, casting sequence mixing as exact Bayesian filtering with the Kalman filter as the core primitive. Classical Kalman filters give principled state and uncertainty estimates but are viewed as inherently sequential; we show that reparameterising them in information form turns their updates into an associative scan - so the per-token recurrent update is non-linear (a Möbius/precision recursion) yet remains temporally parallel. The resulting Kalman Linear Attention (KLA) layer is a drop-in sequence mixer that performs time-parallel probabilistic inference, carries an explicit belief-state uncertainty, and is strictly more expressive than GLA-style linear updates at the same computational cost. This expressivity translates directly into stronger state tracking: KLA solves permutation-composition ($A_5$) tasks that linear SSMs and attention cannot, while staying scan-parallel. As a drop-in primitive it also matches or improves on modern SSMs and GLAs across synthetic token-manipulation and zero-shot commonsense benchmarks, and is among the first stacked Bayesian-filtering primitives trained at the billion-token scale.

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

Heterogeneous Knowledge Distillation via Geometry Decoupling and Momentum-Aware Gradient Regulation

Heterogeneous Knowledge Distillation (HKD) aims to transfer knowledge across varying architectures (e.g., from Transformer to CNN) but inherently suffers from severe training instability. We reveal that this instability stems from two highly coupled challenges: massive feature norm discrepancies that cause optimization drag, and severe gradient conflicts between the primary and distillation objectives arising from distinct inductive biases. To achieve stable distillation, we propose SPOFA, a framework built upon a novel Feature and Gradient Dual Stabilization mechanism. Specifically, at the feature level, we introduce a LayerNorm-based decoupling projector that explicitly decouples feature magnitude from direction, creating a bounded and stable space for semantic alignment. At the gradient level, we propose a momentum-driven Exponential Moving Average (MEMA) dynamic scaler. By establishing a robust historical baseline of the optimization trajectory, MEMA actively evaluates instantaneous gradient conflicts and adaptively penalizes harmful distillation signals, guaranteeing stable convergence. Importantly, SPOFA achieves this dual stabilization with an extremely lightweight parameter footprint. Extensive experiments on two mainstream benchmarks demonstrate that SPOFA achieves state-of-the-art accuracy, significantly outperforming computationally expensive methods while introducing only minimal computational overhead compared to standard baselines.

04.
medRxiv (Medicine) 2026-06-18

Device assessed 24-hour movement behaviour and cardiovascular disease mortality amongst cancer survivors.

Background: Cancer survivors face elevated risks of mortality from cardiovascular disease (CVD). The potential importance of physical activity (PA) and other behaviours across the 24-hour day (e.g. sedentary behaviour (SB) and sleep) for CVD-mortality risk is not well understood in this at-risk population. Objectives: To assess the importance of 24-hour movement behaviour, using a compositional approach, for mitigating CVD-mortality amongst cancer survivors. Methods: Participants with a prior cancer diagnosis were drawn from the UK Biobank accelerometry sub-study (n=6,158). Accelerometer-derived movement (moderate-to-vigorous PA (MVPA), vigorous PA (VPA), moderate PA (MPA), light PA (LPA), SB, sleep) was examined in relation to CVD-mortality, identified from health record linkage data (using Fine-Gray Cox proportional-hazards models adjusted for demographic, health, lifestyle covariates). Results: Median follow-up was 8.0 years (Q1-Q3: 7.4-8.5), with n=500 (8.2%) deaths (CVD-deaths: n=118). Greater MVPA, in place of any other behaviour, was inversely associated with CVD-mortality with e.g. 10% lower hazard if MVPA theoretically replaced 7 minutes (mins)/day SB (Hazard ratio (HR): 0.91, (95% Confidence Interval: 0.86-0.95)), 9 mins/day LPA (HR: 0.90, 0.83-0.97), or 11 mins/day sleep (HR: 0.90, 0.83-0.97). The VPA component of MVPA proved critical, requiring only ~1-2 additional mins/day for equivalent hazard reduction. Sleep duration, was also inversely associated with CVD-mortality. A 10% lower hazard required replacing 29 mins/day of SB with sleep (HR: 0.90, 0.84-0.96); no other behavioural replacement amongst SB, sleep or LPA could provide an equivalent risk reduction. Conclusions: Among cancer survivors, the most potent reduction in CVD-mortality followed theoretically reallocating time to higher intensity movement.

05.
arXiv (CS.CV) 2026-06-19

3D-PLOT-LLM: Part-Level Object Tokens for 3D Large Language Models

3D multimodal large language models (3D MLLMs) describe a 3D object as a whole but cannot address, name, or reason about its parts. Prior part-aware attempts add segmentation decoders, heavier 3D encoders, or bounding-box grammars at substantial parameter cost. We take a fundamentally different path: we reorganize the input token stream so that parts become directly addressable through the LLM's own vocabulary. Our model, 3D-PLOT-LLM, partitions the frozen point encoder's patches into K locally coherent regions and inserts, before each region's patch tokens, a learnable per-region marker and a reserved vocabulary token ; a Marker-Space Refinement (MSR) module then conditions each marker on its region's spatial statistics and adjacency neighbors. The model thus cites parts in its output and follows prompts that refer to parts by token, a capability absent from prior object-level 3D MLLMs. To probe this interface, we construct PartVerse-QA, a vocabulary-level part-QA benchmark adapted from PartVerse mesh annotations (77K training pairs and 588 held-out queries on disjoint object splits), on which 3D-PLOT-LLM reaches caption-to-slots Jaccard 0.459 and Exact-match 13.78%, with a slot-to-caption GPT-4o judge of 44.68. On the 3DCoMPaT-GrIn part-aware grounded description benchmark, 3D-PLOT-LLM outperforms PointLLM, Kestrel, PARIS3D, and SegPoint on every text-output metric, and ShapeLLM on 3 of 4, with up to +3.03 GPT-4o judge over PointLLM. On Objaverse whole-object captioning, adding PartVerse-QA at Stage 2 yields +0.65 SBERT and +1.85 GPT-4o over PointLLM, and tops PointLLM-PiSA on 4 of 5 traditional metrics (SBERT, SimCSE, BLEU-1, METEOR) despite targeting a different (part-grounded) objective. All with under 1M new trainable parameters on a frozen point encoder, an order of magnitude below prior part-aware 3D MLLMs, and no segmentation decoder or bounding-box head.

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

Hierarchical Fine-Grained Aerial Object Detection

Fine-grained aerial object detection, driven by the intrinsic granularity of real-world object categories, is crucial for advanced scene understanding in remote sensing. Existing methods largely inherit the paradigm of coarse-grained object detection, relying solely on single-label supervision and thus struggling to distinguish model-level categories with subtle structural differences. However, for each specific model (e.g., Boeing 787), structured prior knowledge such as attributes and hierarchies offers discriminative semantics across multiple granularities. Motivated by this, we present ExpertDet, a scheme that incorporates expert-informed cues to enhance fine-grained aerial object detection. Specifically, we design Vision-aware Masked Attribute Modeling (VMAM), which aligns attribute semantics with visual structures by reconstructing randomly masked attributes from visual cues, enabling the detector to capture subtle structural distinctions. We further propose Hierarchical Visual Instance Promotion (HierVIP), which builds a visual prototype tree based on hierarchical relations and imposes taxonomy-aware constraints to preserve cross-level semantic continuity while enhancing category discrimination. Moreover, we curate a new fine-grained object detection benchmark for Precise recognition of model-specific Ships and Planes from aerial imagery, PSP, covering 106 ship classes and 30 airplane models, respectively, featuring the most extensive collection of model-specific categories among existing aerial object detection datasets to date. We benchmark state-of-the-art object detection algorithms on the PSP benchmark. Extensive evaluation demonstrates that ExpertDet consistently outperforms other fine-grained competitors across hierarchy levels. The dataset, benchmark, and code are available at https://nnnnerd.github.io/PSP-Benchmark/.

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

ENPIRE: Agentic Robot Policy Self-Improvement in the Real World

arXiv:2606.19980v1 Announce Type: new Abstract: Achieving dexterous robotic manipulation in the real world heavily relies on human supervision and algorithm engineering, which becomes a central bottleneck in the pursuit of general physical intelligence. Although emerging coding agents can generate code to automate algorithm search, their successes remain largely confined in digital environments. We conjecture that the missing abstraction to automate robotics research is a repeatable feedback loop for real-world policy improvement: reset the scene, execute a policy, verify the outcome, and refine the next iteration. To bridge this gap, we introduce ENPIRE, a harness framework for coding agents that instantiates this physical feedback routine with four core modules: an Environment module (EN) for automatic reset and verification, a Policy Improvement module (PI) that launches policy refinement, a Rollout module (R) to evaluate policies with one or multiple physical robots operating in parallel, and an Evolution module (E) in which coding agents analyze logs, consult literature, improve training infrastructure and algorithm code to address failure modes. This closed-loop system transforms real-world manipulation learning into a controllable optimization procedure, minimizing human effort while allowing fair ablations across training recipe and agent variants. Powered by ENPIRE, frontier coding agents can autonomously train a policy to achieve a 99% success rate on challenging, dexterous manipulation tasks, such as organizing a pin box, fastening a zip tie, and tool use, a process that further accelerates when we dispatch an agent team on a robot fleet. Our results suggest a practical and scalable path toward deploying coding agents to autonomously advancing robotics in the physical world.

08.
arXiv (CS.CV) 2026-06-18

Hybrid Transformer-Mamba for Weakly Supervised Volumetric Medical Segmentation

Weakly supervised segmentation enables model training from plane-level labels. Existing methods often rely on 2D encoders, neglecting the volumetric nature of medical data. We propose TranSamba, a hybrid Transformer-Mamba architecture designed to capture 3D context via cross-plane modeling. TranSamba augments a Vision Transformer backbone with Cross-Plane Mamba blocks, leveraging linear-time modeling for efficient information exchange across neighboring planes. This exchange improves in-plane self-attention and subsequent attention maps for object localization. TranSamba maintains linear time complexity and constant space complexity with respect to the input volume depth. Extensive experiments on three datasets covering diverse modalities and pathologies show that TranSamba achieves state-of-the-art performance, demonstrating the generalizable efficacy of cross-plane modeling. Code is available at: https://github.com/YihengLyu/TranSamba.

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

Instance-Aware Knowledge Distillation for Semi-Supervised Learning of an On-Board Multi-Task Dense Prediction Model for Collision Avoidance System

Collision avoidance systems have evolved toward camera-based deep learning approaches for driving scene understanding. However, deployment in edge environments such as country clubs is constrained by limited computational resources and unreliable communication infrastructure. Moreover, constructing large-scale datasets for the target domain involves substantial annotation cost. To address these limitations, we propose an instance-aware knowledge distillation framework for semi-supervised learning. Specifically, we generate pseudo labels that mitigate teacher bias by leveraging domain priors from the teacher and instance-centric knowledge from foundation models. The trained lightweight student is deployed in the proposed collision avoidance system and performs multiple dense prediction tasks in real-time. The system detects frontal obstacles and encodes their spatial information into controller area network messages for automated guided vehicle operation. To achieve this, we construct a large-scale country club dataset and perform field validation of the proposed system. Experimental results demonstrate that the student outperforms the large teacher in instance segmentation while mitigating performance degradation in monocular depth estimation. Compared with the teacher, the student reduces FLOPs by 22.68$\times$ and parameters by 14.33$\times$, achieving 6.46 FPS on a low-cost edge device.

10.
arXiv (CS.LG) 2026-06-18

Anti-causal domain generalization: Leveraging unlabeled data

arXiv:2602.17187v2 Announce Type: replace-cross Abstract: The problem of domain generalization concerns learning predictive models that are robust to distribution shifts when deployed in new, previously unseen environments. Existing methods typically require labeled data from multiple training environments, limiting their applicability when labeled data are scarce. In this work, we study domain generalization in an anti-causal setting, where the outcome causes the observed covariates. Under this structure, environment perturbations that affect the covariates do not propagate to the outcome, which motivates regularizing the model's sensitivity to these perturbations. Crucially, estimating these perturbation directions does not require labels, enabling us to leverage unlabeled data from multiple environments. We propose two methods that penalize the model's sensitivity to variations in the mean and covariance of the covariates across environments, respectively, and prove that these methods have worst-case optimality guarantees under certain classes of environments. Finally, we demonstrate the empirical performance of our approach on a controlled physical system and a physiological signal dataset.

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

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

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.

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

Separable Neural Architectures as Physical World Models: from Mathematical Theory to Applications

arXiv:2606.14934v1 Announce Type: cross Abstract: This work introduces the Separable Neural Architecture (SNA), a function representational class combining neural approximation with tensor decomposition. The SNA decouples localized coordinate functions (atoms) from global interactions governed by a sparse, low-rank interaction object. This architecture possesses a compact and smooth inductive bias well-suited for solving partial differential equations (PDEs). When viewed as a Galerkin trial space under the variational SNA (VSNA) framework, the formulation satisfies classical variational guarantees under Lax-Milgram: well-posedness, quasi-optimality, convergence, and stability. In high-dimensional spatiotemporal–parametric PDEs, the VSNA mitigates the curse of dimensionality by scaling algebraically rather than exponentially. Exploiting an entirely factorized, tensor-native alternating least squares (ALS) optimization framework reduces this cost to linear in dimension. The VSNA is validated across elliptic, hyperbolic, and parabolic systems, demonstrating close alignment with predicted algebraic and spectral scaling rates. We showcase the SNA as a "solve once, query anywhere" physical world model via two engineering case studies: a 7D parametric manufacturing simulation and an experimental thermal-to-property inversion pipeline for Inconel 718. The VSNA executes a 1,000,000-query Monte Carlo sweep in 102s on a standard laptop CPU, yielding a 150,000x speedup over a full-grid finite element baseline hosted on an NVIDIA A100 GPU. It further enables real-time generative inverse-mode reconstructions under 100ms. These results demonstrate that the SNA serves as a compact mathematical substrate for continuous parameter manifolds to enable real-time inversion, optimization loops, and rapid uncertainty propagation.

13.
arXiv (CS.CV) 2026-06-12

InterleaveThinker: Reinforcing Agentic Interleaved Generation

Recent image generators have demonstrated impressive photorealism and instruction-following capabilities in single-image generation and editing. However, constrained by their architectures, they cannot achieve interleaved generation (text-image sequence), which has crucial applications in visual narratives, guidance, and embodied manipulation. Even the latest open-source Unified Multimodal Models (UMMs) exhibit limited performance in this regard. In this paper, we introduce InterleaveThinker, the first multi-agent pipeline designed to endow any existing image generator with interleaved generation capabilities. Specifically, we employ a planner agent to organize the image-text input sequence, instructing the image generator on the required execution at each step. Subsequently, we introduce a critic agent to evaluate the generator's outputs, identify samples that deviate from the planned instructions, and refine the instructions for regeneration. To implement this pipeline, we construct the Interleave-Planner-SFT-80k and Interleave-Critic-SFT-112k to perform a format cold-start. Then we develop Interleave-Critic-RL-13k to reinforce the step-wise instruction correction capability within a generation trajectory using GRPO. Since a single interleaved generation trajectory may involve over 25 generator calls, optimizing the entire trajectory is computationally impractical. Therefore, we propose accuracy reward and step-wise reward, allowing single-step RL to effectively guide the entire generation trajectory. The results show that InterleaveThinker improves performance across various image generators. On interleaved generation benchmarks, it achieves performance comparable to Nano Banana and GPT-5. Surprisingly, it also significantly enhances the base model on reasoning-based benchmarks; for example, on 4-step FLUX.2-klein, we observe substantial gains on WISE and RISE.

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

Learner-based Concept Drift Detection: Analysis and Evaluation

arXiv:2606.20216v1 Announce Type: cross Abstract: Machine learning algorithms deployed for evolving streaming environments must handle the non-stationary data distributions, commonly referred to as concept drift. The presence of concept drift poses a major challenge for many real-world applications because it can severely degrade their predictive performance, hindering their ability to support robust decision-making. Consequently, the timely and efficient detection of drift events is critical for sustaining high accuracy over time. This study examines theoretically the concept drift characteristics and numerous drift detection algorithms across several categories. Furthermore, we evaluate their performance on both synthetic and real-world datasets exhibiting diverse streaming scenarios and drift characteristics, such as abrupt and gradual changes. This study aims to enhance understanding of the complex notion of concept drift characteristics and behavior of drift detectors, along with their applicability to diverse contexts.

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

Proact-VL: A Proactive VideoLLM for Real-Time AI Companions

Proactive and real-time interactive experiences are essential for human-like AI companions, yet face three key challenges: (1) achieving low-latency inference under continuous streaming inputs, (2) autonomously deciding when to respond, and (3) controlling both quality and quantity of generated content to meet real-time constraints. In this work, we instantiate AI companions through two gaming scenarios, commentator and guide, selected for their suitability for automatic evaluation. We introduce the Live Gaming Benchmark, a large-scale dataset with three representative scenarios: solo commentary, co-commentary, and user guidance, and present Proact-VL, a general framework that shapes multimodal language models into proactive, real-time interactive agents capable of human-like environment perception and interaction. Extensive experiments show Proact-VL achieves superior response latency and quality while maintaining strong video understanding capabilities, demonstrating its practicality for real-time interactive applications.

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

NaturalFlow: Reducing Disruptive Pauses for Natural Speech Flow in Simultaneous Speech-to-Speech Translation

Simultaneous speech-to-speech translation aims to enable near-real-time communication by minimizing latency, offering a compelling, real-time alternative to the high latency of consecutive translation. However, the excessive pursuit of low latency often results in fragmented chunk-wise speech. Consequently, listeners are subjected to an unnatural acoustic flow punctuated by frequent pauses, which could increase their cognitive load. To bridge this gap, we introduce a fluency-aware optimization framework designed to discover the sweet spot between the low-latency benefits of simultaneous translation and the natural flow of consecutive translation. Our framework minimizes inter-chunk silences by leveraging model-internal signals, including linguistic diversity and induced temporal variability in speech durations. Experiments on short- and long-form benchmarks show that our framework produces natural speech flow while maintaining competitive latency and translation quality.

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

Imbalanced Semi-Supervised Learning via Label Refinement and Threshold Adjustment

arXiv:2407.05370v3 Announce Type: replace Abstract: Semi-supervised learning (SSL) algorithms often struggle to perform well when trained on imbalanced data. In such scenarios, the generated pseudo-labels tend to exhibit a bias toward the majority class, and models relying on these pseudo-labels can further amplify this bias. Existing imbalanced SSL algorithms explore pseudo-labeling strategies based on either pseudo-label refinement (PLR) or threshold adjustment (THA), aiming to mitigate the bias through heuristic-driven designs. However, through a careful statistical analysis, we find that existing strategies are suboptimal: most PLR algorithms are either overly empirical or rely on the unrealistic assumption that models remain well-calibrated throughout training, while most THA algorithms depend on flawed metrics for pseudo-label selection. To address these shortcomings, we first derive the theoretically optimal form of pseudo-labels under class imbalance. This foundation leads to our key contribution: SEmi-supervised learning with pseudo-label optimization based on VALidation data (SEVAL), a unified framework that learns both PLR and THA parameters from a class-balanced subset of training data. By jointly optimizing these components, SEVAL adapts to specific task requirements while ensuring per-class pseudo-label reliability. Our experiments demonstrate that SEVAL outperforms state-of-the-art SSL methods, producing more accurate and effective pseudo-labels across various imbalanced SSL scenarios while remaining compatible with diverse SSL algorithms. The code is publicly available (https://github.com/ZerojumpLine/SEVAL).

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

Beyond Classification: A Cough Regression Benchmark for Respiratory Acoustic Foundation Models

arXiv:2606.15436v1 Announce Type: cross Abstract: Respiratory acoustic foundation models (FMs) excel at cough classification, yet their ability to predict continuous health quantities from cough audio remains largely unexplored, despite the clinical value of passive age, BMI, and disease probability estimation in settings where physical measurements are unavailable. We introduce the multi-model, multi-target cough regression benchmark evaluating five FMs (OPERA-CT, OPERA-CE, OPERA-GT, HeAR, M2D+Resp) across six targets on three datasets under subject-disjoint protocols, comparing linear, MLP-small, and full MLP regression heads. MLP-small beats the mean-predictor baseline on all tasks and linear probing in 23 of 30 model x task cases, with full MLP overfitting on small clinical data but recovering on larger sets, revealing a dataset size x head-capacity trade-off. HeAR leads within-dataset age regression on Coswara (9.12 yr MAE); its CIDRZ result is excluded from headline claims owing to possible HeAR-CIDRZ pretraining overlap. OPERA-GT is favored over OPERA-CT on age in all three datasets, with the CIDRZ margin within seed variance, extending a generative-pretraining advantage from breath to cough. HeAR and M2D+Resp reach near-full performance at N = 50 samples while OPERA models require N = 400. Cross-dataset transfer is strongly asymmetric as large diverse data generalises to small clinical populations (CoughVID to CIDRZ: -0.17 yr) but not vice versa (CIDRZ to Coswara: +2.43 yr, +26.6%).

20.
Nature (Science) 2026-06-10

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

作者:

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.

21.
arXiv (CS.CL) 2026-06-24

Speculative Pipeline Decoding: Higher-Accruacy and Zero-Bubble Speculation via Pipeline Parallelism

Speculative Decoding (SD) accelerates low-concurrency LLM inference by employing a draft-then-verify paradigm. However, mainstream methods typically rely on multi-token prediction, which introduces escalating prediction difficulty and serial drafting latency. To address these, we propose Speculative Pipeline Decoding (SPD), a groundbreaking framework that unlocks the true potential of pipeline parallelism. By partitioning the target LLM into $n$ pipeline stages, SPD allows LLM to process $n$ tokens within single sequence in parallel to accelerate decoding. To continuous fill the pipeline in single sequence decoding, a speculation module aggregates intermediate features across different pipeline depths to predict the next token, executing strictly in parallel with the target model's pipeline step, to realize bounded difficulty, higher acceptance rates, and zero latency bubbles. Our experiments demonstrate that SPD achieves significantly higher theoretical and wall-clock speedup compared to mainstream baselines at moderate pipeline depth, though more aggressive settings require further improvement. Our code is available at https://github.com/yuyijiong/speculative_pipeline_decoding

22.
arXiv (CS.AI) 2026-06-17

Fixed-Point Reasoners: Stable and Adaptive Deep Looped Transformers

arXiv:2606.18206v1 Announce Type: new Abstract: Looped architectures provide an inductive bias toward learning step-by-step procedures for tasks that require compositional reasoning. The number of effective layers reached by looping determines the quality of the solution these models find. Like deep architectures, looped architectures are prone to a signal propagation problem induced by depth as the halting decision is postponed. In this paper, we address this signal propagation issue using pre-norm layers and residual scaling. Building on these architectural modifications, we propose FPRM, a Transformer-based Fixed-Point Reasoning Model that uses fixed-point convergence as an end-to-end halting mechanism in a looped architecture. We show that fixed-point halting allows FPRM to adapt its compute to task difficulty. FPRM is effective on common reasoning benchmarks, namely Sudoku, Maze, state-tracking, and ARC-AGI.

23.
arXiv (CS.AI) 2026-06-11

Estimating Tail Risks in Language Model Output Distributions

arXiv:2604.22167v2 Announce Type: replace-cross Abstract: Language models are increasingly capable and are being rapidly deployed on a population-level scale. As a result, the safety of these models is increasingly high-stakes. Fortunately, advances in alignment have significantly reduced the likelihood of harmful model outputs. However, when models are queried billions of times in a day, even rare worst-case behaviors will occur. Current safety evaluations focus on capturing the distribution of inputs that yield harmful outputs. These evaluations disregard the probabilistic nature of models and their tail output behavior. To measure this tail risk, we propose a method to efficiently estimate the probability of harmful outputs for any input query. Instead of naive brute-force sampling from the target model, where harmful outputs could be rare, we operationalize importance sampling by creating unsafe versions of the target model. These unsafe versions enable sample-efficient estimation by making harmful outputs more probable. On benchmarks measuring misuse and misalignment, these estimates match brute-force Monte Carlo estimates using 10-20x fewer samples. For example, we can estimate probability of harmful outputs on the order of 10^-4 with just 500 samples. Additionally, we find that these harmfulness estimates can reveal the sensitivity of models to perturbations in model input and predict deployment risks. Our work demonstrates that accurate rare-event estimation is both critical and feasible for safety evaluations. Code is available at https://github.com/rangell/LMTailRisk

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

When Does Streaming Tool Use Help? Characterizing Tool-Intent Stabilization in Streaming Retrieval-Augmented Generation

Streaming Retrieval-Augmented Generation (Streaming RAG) reduces user-perceived latency by issuing tool queries in parallel with ongoing user input, before the utterance is complete. Reported gains are aggregate, yet the mechanism's benefit is fundamentally query-intrinsic: speculation can only help when the correct tool query becomes determinable before the user stops speaking or typing. We isolate and measure this property – tool-intent stabilization, the point in the input stream at which a speculative query's retrieval converges to the answer-bearing result. On the CRAG benchmark (1371 validation questions) we (i) measure the distribution of stabilization, (ii) derive a model-agnostic bound H on the portion of tool latency that can be hidden behind the user's remaining input, as a function of tool latency L and input cadence {\delta}, (iii) validate against a working streaming pipeline that realized savings meet or exceed this bound, and (iv) identify which query properties predict early versus late stabilization. The study requires no model training and runs on commodity CPU hardware. We find that at a realistic operating point (L=600ms, {\delta}=3w/s, {\theta}=0.8), 73.9% of queries across the full benchmark admit substantial latency hiding – a blended figure that mixes sufficiency stabilization on the 21.3% of questions where gold evidence is verbatim-present and BM25-retrievable (95.2% streamable on this favorable slice) with a grounding-free top-1-settling fallback on the remainder. On the favorable slice, {\phi}_suf is bracketed to [0.26, 0.281] by exact and relaxed grounding – both early. Question type produces a significant but coarse early/late split (Kruskal-Wallis p=0.017, epsilon^2=0.04), directly informing when a learned speculative trigger is worth its cost.