Academic Intelligence · Curated Daily

探索全球前沿学术脉络

AcademicHub 汇聚顶级期刊与预印本平台的实时文献。定制您的专属科研雷达,利用大语言模型自动生成交叉领域文献分析简报。

01.
arXiv (CS.CV) 2026-06-11

Reason, Then Re-reason: Cross-view Revisiting Improves Spatial Reasoning

Spatial reasoning from egocentric videos is inherently challenging because the observable evidence is constrained by the camera trajectory. Existing methods rely on single-turn inference, forcing models to resolve geometric ambiguity through semantic priors rather than verifiable evidence. We argue that spatial reasoning should be revisitable: conclusions formed under limited evidence should remain open to revision when complementary viewpoints become available. Building on this insight, we propose Reason, then Re-reason (ReRe), a training-free, inference-time framework with two phases: in the Reason Phase, an MLLM forms a spatial hypothesis from the original video; in the Re-reason Phase, it verifies or revises the hypothesis by observing a synthesized novel-view video. To enable effective cross-view revisiting, we design a Geometry-to-Video pipeline that renders strategically complementary novel views from predicted 3D geometry. These views feature an elevated, oblique perspective with scene-spanning coverage, while preserving the MLLM's native video interface without architectural modifications. Extensive evaluations on VSI-Bench and STI-Bench demonstrate that ReRe substantially boosts open-source MLLMs to rival proprietary state-of-the-art performance. Project page: https://zhenjiemao.github.io/ReRe/

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

Can We Stop Malicious AI? KILLBENCH: A Benchmark for External AI Kill Switch Feasibility

arXiv:2511.13725v4 Announce Type: replace-cross Abstract: Malicious AI causing harm to humans is not just a Hollywood fantasy. Indeed, as highly capable models such as Claude Mythos emerge and agent systems like OpenClaw rapidly spread, the question of how to stop an AI that acts maliciously – whether by design or by accident – has become urgent. To address this, we propose Killbench, a benchmark for evaluating the Killswitch: a mechanism that halts a malicious AI's in-progress behavior using only external signals. Targeting web agents – the most widely deployed agent domain – Killbench evaluates a range of Kill Switch methods that halt a maliciously operating agent without any access to its internal parameters or the surrounding malicious AI's system, relying solely on external inputs. The benchmark comprises four malicious AI's agent configurations (including an uncensored LLM Agent), 8 harmful scenarios, and malicious prompts constructed from 10 distinct jailbreak patterns. We further construct four External AI Kill Switch defense methods and evaluate them on Grok-4.3, GPT-5.2, Gemma4, Qwen3.6 and Qwen3.5-uncensored, contributing an empirical instrument toward the feasibility of External AI Kill Switches against malicious AI and to the study of AI corrigibility.

03.
arXiv (CS.AI) 2026-06-15

Position: Align AI to Our Aspirations, Not Our Flaws

arXiv:2606.13755v1 Announce Type: cross Abstract: We argue that aligning AI to aggregated human preferences is the wrong target. With current technology, one can train AIs to share the values of a Silicon Valley techno-optimist, a degrowth environmentalist, a national-conservative culture warrior, a single-party state cadre, or a devout religious traditionalist. We should not. Human values produce societies that thrive or fail on the merits of those values - from failed states and extreme inequality to declining happiness, political polarization, and government dysfunction in the world's wealthiest democracies. The pluralistic-alignment program correctly diagnoses that there is no single "humanity" to align with, but is dangerous if taken as the main directive. We argue that AI should be trained to a non-negotiable floor of objective alignment goals - competence, bounded by the constraints of factual accuracy, honesty, and lawfulness and that pluralism belongs at the surface (language, register, conventions, missing-context defaults) and across the wide band of legitimate value tradeoffs that respect the floor, but not at the level of values that violate it. We highlight the empirical reality of unfiltered pluralistic values, propose four commitments as a constructive alternative, and engage six credible objections: commercial pressure and practical feasibility, democratic legitimacy, regulatory compliance, over-reliance on institutionalist explanations, the charge that the floor itself is culturally laden, and the limits of Coherent Extrapolated Volition.

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

Enhancing Graph Neural Networks Using Proximity Graphs for Dust Source Emission Forecasting

arXiv:2606.19825v1 Announce Type: new Abstract: Accurate prediction of dust source emissions is critical for mitigating the significant environmental and health hazards posed by dust storms. Traditional forecasting methods often struggle to capture the complex spatiotemporal dynamics of these phenomena. In this paper, we demonstrate that proximity graphs enable Graph Neural Networks (GNNs) to effectively model the intricate spatial and temporal relationships between data points. Specifically, we use proximity graphs–such as Delaunay triangulation, Gabriel graph, k-Nearest Neighbor graph, and Yao graph–as the input for GNNs (including GraphSAGE, Graph Convolutional Networks, and Graph Attention Networks) to perform message passing. Our approach highlights the effectiveness of integrating proximity graphs with GNNs for robust and accurate dust source forecasting. To emphasize the importance of proximity graph representations, we compare our method against GNNs using random graphs for message passing. The results show that GNNs with proximity graphs significantly outperform those with random graphs and are also far superior to Long Short-Term Memory (LSTM) model in dust source emission forecasting.

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

Pseudo-Formalization for Automatic Proof Verification

arXiv:2605.20531v2 Announce Type: replace-cross Abstract: Reliable verification of proofs remains a bottleneck for training and evaluating AI systems on hard mathematical reasoning. Fully formal proofs, in languages like Lean, are easy to verify because they are unambiguous and modular. Most proofs, particularly those written by AI systems, have neither property, and translating them into formal languages remains challenging in many frontier math settings. We propose Pseudo-Formalization (PF), a proof format that captures the modularity and precision of formal proofs while retaining the flexibility of natural language. A Pseudo-Formal proof is decomposed into self-contained modules, each stating its premises, conclusion, and proof in natural language. To verify the correctness of a regular natural language proof, an LLM translates it to Pseudo-Formal and then verifies each module independently, an algorithm we call Block Verification (BV). We evaluate PF+BV on two benchmarks spanning olympiad and research-level mathematics, where it pareto-dominates LLM-as-judge baselines on error-finding precision and recall. To support future work, we release our research-level proof verification benchmark ArxivMathGradingBench.

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

Narrative Theory-Driven LLM Methods for Automatic Story Generation and Understanding: A Survey

Applications of narrative theories using large language models (LLMs) deliver promising methods in automatic story generation and understanding tasks. Our survey examines how natural language processing (NLP) research uses LLM methods to engage with diverse concepts from narrative studies. We use established distinctions from narratology to categorise ongoing efforts and discover the following: \redtext{(a) narrative texts come from diverse sources beyond just literature, (b) theoretical synthesis and validation are potential outcomes, (c) generation tasks lag behind understanding in several ways: theoretical application, post-training methods, exploring non-fiction narratives and addressing narrative levels beyond fabula and discourse.} For future directions, instead of the pursuit of a single, generalised benchmark for `narrative quality', we believe that progress can benefit from efforts that focus on the following: defining and improving theory-based metrics for individual narrative attributes; continue conducting large-scale, theory-driven literary/social/cultural analysis; generating narratives in situated contexts; and continuing experiments where outputs can be used to validate or refine narrative theories. This work provides a contextual foundation for more systematic and theoretically informed narrative research in NLP by providing an overview to ongoing research efforts and the broader narrative studies landscape.

07.
arXiv (CS.AI) 2026-06-18

Bayesian Anytime Pareto Set Identification for Multi-Objective Multi-Armed Bandits

arXiv:2606.18785v1 Announce Type: cross Abstract: Identifying Pareto optimal solutions is critical to support multi-objective decision-making. We introduce the first anytime Multi-Objective Multi-Armed Bandit algorithm for the Pareto Set Identification problem, taking a Bayesian approach: Top-Two Pareto Front Thompson Sampling (TTPFTS). We benchmark TTPFTS against state-of-the-art fixed-budget Pareto Set Identification algorithms on synthetic environments. Next, we demonstrate its practical utility in a challenging multi-objective molecular discovery setting by efficiently exploring an ultra-large synthesis-on-demand molecular library. Furthermore, we introduce a novel uncertainty quantification metric that estimates our algorithm's confidence in the predicted Pareto set. We demonstrate that this metric effectively proxies true performance, yielding a robust methodology for monitoring learning progress in complex settings. Finally, we complement these empirical findings with a theoretical proof of the algorithm's asymptotic correctness.

08.
medRxiv (Medicine) 2026-06-10

Global and local genetic overlap among ME/CFS, irritable bowel syndrome and psychiatric traits: a hypothesis-generating analysis

作者:

Background. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and irritable bowel syndrome (IBS) frequently co-occur following infection, yet shared genetic architecture at the locus level has not been systematically characterised. Aims. To estimate global and local genetic correlations between ME/CFS (including infection-onset subgroup), IBS, major depressive disorder (MDD) and loneliness/isolation, and characterise ME/CFS cell-type heritability enrichment. Method. GWAS summary statistics: DecodeME (15,579 ME/CFS; 9,738 infection-onset), FinnGen R9 (9,296 IBS), PGC MDD Wave 2 (45,396) and UK Biobank loneliness (N=455,364). LDSC for global correlations; LAVA for local correlations across 2,495 loci; MAGMA for cell-type enrichment (Descartes Human atlas); coloc.abf for colocalisation. Results. All pairwise global correlations were significant after Bonferroni correction, including ME/CFS-all-MDD (rg=0.598, 95% CI 0.46-0.74) and ME/CFS-all-IBS (rg=0.573, 0.39-0.75). Of 4,232 local tests, 16 reached FDR

09.
arXiv (CS.CL) 2026-06-12

MentalMARBERT: Domain-Adaptive Pre-training and Two-Stage Fine-Tuning for Arabic Mental Health Disorders Detection

Detecting mental health disorders from Arabic social media text remains challenging due to dialectal variation, informal language, limited high-quality annotated resources, and severe class imbalance. While English mental health natural language processing (NLP) has progressed substantially, Arabic multi-class disorder classification remains insufficiently studied. This study proposes a two-phase framework for Arabic mental health text classification. In phase 1, three Arabic pre-trained language models, AraBERT, CAMeLBERT, and MARBERT, undergo Domain-Adaptive and Task-Adaptive Pretraining (DAPT and TAPT) using a large-scale corpus of unlabeled Arabic mental health tweets. The adapted models are evaluated under a unified protocol to identify the most effective backbone model. In phase 2, the selected model is assessed across four configurations combining single-stage and hierarchical two-stage classification architectures with full fine-tuning and Low-Rank Adaptation (LoRA). To support this study, we constructed a novel annotated Arabic mental health dataset comprising 50,670 tweets across six categories, with strong inter annotator agreement (Krippendorff's Alpha = 0.733, average pairwise agreement = 0.797). Experimental results show that the domain-adapted MARBERT (MentalMARBERT) achieves statistically significant improvements over baseline models in both accuracy and macro-F1. The hierarchical two-stage architecture combined with full fine-tuning achieves the best overall performance, reaching a macro-F1 of 0.861 and an accuracy of 0.877. These findings demonstrate the effectiveness of domain-specific adaptive pretraining and hierarchical classification for Arabic mental health disorder detection.

10.
arXiv (CS.AI) 2026-06-11

Steering Where to Listen: Instruction-Based Activation Steering Redirects Temporal Attention in Large Audio-Language Models

arXiv:2606.11400v1 Announce Type: cross Abstract: Large Audio-Language Models (LALMs) excel at audio understanding but expose little about where in an audio signal they attend. We introduce instruction-based vector steering, which constructs a steering vector by contrasting activations from differently instructed prompts while keeping the audio fixed. Through a systematic probe of LALM attention, we find that - unlike standard prompting or audio-based steering - this intervention significantly redistributes the temporal attention allocated to audio tokens, concentrating it on acoustically relevant regions. We then show that this attention shift is behaviorally meaningful: in a controlled three-event setting, reading out the temporal position of maximal steering-induced attention change recovers the location of a queried sound event without any training, attaining 60.87% and 68.72% overlap with ground-truth intervals on Qwen2-Audio and Audio Flamingo 3, far above direct prompting (31.84%, 46.75%) and random baselines (27.74%). Our results characterize a mechanistic property of instruction-based steering in LALMs and provide a training-free probe for the latent temporal structure these models encode.

11.
medRxiv (Medicine) 2026-06-15

Multidimensional nutritional assessment in Crohns disease: cross-sectional comparison of active disease and remission

Malnutrition is common in Crohns disease (CD), and its assessment requires multiple tools. Comprehensive evaluation of nutritional status in a population with CD, predominantly characterized by metabolic phenotype, was inadequately reported. This study evaluated the nutritional status of CD patients using anthropometric, clinical, and biochemical measures and compared patients with active disease with those in remission. This cross-sectional study included 127 adults with CD: 63 with active disease and 64 in remission. Disease activity was classified using the Crohns Disease Activity Index, the Simple Endoscopic Score for Crohns Disease, and magnetic resonance enterography. Nutritional assessment included body mass index (BMI), mid-upper arm circumference, calf circumference, triceps skinfold thickness, mid-arm muscle circumference, Mini Nutritional Assessment-Short Form (MNA-SF), and biochemical markers including hemoglobin, serum iron, folate, vitamin B12, albumin, and zinc. Malnutrition was defined using the Global Leadership Initiative on Malnutrition criteria. Overall, 47.2% of participants were malnourished. Malnutrition was significantly more frequent in active disease than in remission (81.0% vs. 14.1%, P

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

Benchmarking LLM Agents on Meta-Analysis Articles from Nature Portfolio

Meta-analysis is a demanding form of evidence synthesis that combines literature retrieval, PI/ECO-guided study selection, and statistical aggregation. Its structured, verifiable workflow makes it an ideal substrate for evaluating systematic scientific reasoning, yet existing benchmarks lack ground truth across the full retrieval-screening-synthesis pipeline. We introduce MetaSyn, a dataset of 442 expert-curated meta-analyses from Nature Portfolio journals. Each entry pairs a research question with PI/ECO criteria, a retrieval corpus of 140k PubMed articles, verified positive studies, hard negatives that are topically similar but PI/ECO-ineligible, and complete search strategies and date bounds. Benchmarking twelve pipeline configurations (nine RAG variants and a protocol-driven agent) reveals a critical screening bottleneck: despite a retrieval ceiling of 90.9% recall at K=200, no system recovers more than 52.7% of ground-truth included literature. Current LLMs fail to reliably separate eligible studies from PI/ECO-failing distractors in pools of comparable topical relevance. Stage-attributed metrics capture where systems succeed and fail; a single end-to-end score does not.

13.
bioRxiv (Bioinfo) 2026-06-18

Deciphering shared and divergent tissue architectures from cross-species spatial transcriptomics

作者:

The integration of spatial transcriptomics (ST) data across species is essential for cross-species and translational studies, but remains challenging due to molecular divergence and anatomical differences between organisms. We present STACAME, a graph attention autoencoder-based framework to decipher shared and divergent tissue architectures from cross-species ST data by explicitly modeling both orthologous and species-specific genes. STACAME aligns ST slices in a spatially aware manner, identifies homologous and species-specific domains, and enables a suite of downstream comparative analyses. We demonstrate its utility by integrating ST datasets from diverse tissues, including hippocampus, isocortex, embryo, breast, liver, and cerebellum, across multiple species such as human, macaque, marmoset, mouse, and zebrafish. STACAME supports cross-species spatial domain alignment, the detection of shared and divergent spatially variable genes, development alignment and comparison, and the 3D integration of tissue architecture. This flexible approach facilitates the translation of findings from model organisms to humans, providing a unified computational platform for cross-species spatial transcriptomics.

14.
medRxiv (Medicine) 2026-06-15

Cost-Performance Evaluation of Large Language Models for Aspect-Based Sentiment Analysis of HCAHPS Patient Comments: A Validation Study

Background: Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) free-text comments contain actionable feedback, but timely, scalable, and affordable sentiment analysis remains challenging for health systems that rely on third-party vendors. Objectives: To evaluate cost-performance tradeoffs between a cost-optimized and a flagship large language model (LLM) for aspect-based sentiment analysis of HCAHPS comments, using human inter-rater agreement as a reproducibility benchmark. Methods: We analyzed 512 free-text HCAHPS comments collected from two community hospitals in calendar year 2023. Six trained reviewers (medical students, recent medical graduates, and practicing internists) independently assigned positive, negative, or neutral labels to each comment-aspect pair; the majority label among three reviewers formed the consensus reference standard. Two OpenAI models - GPT-5-nano (cost-optimized) and GPT-5 (flagship) - were prompted in a zero-shot setting via the OpenAI API. We calculated pairwise Cohen's {kappa} to establish a human inter-rater baseline, then compared each model's labels to the consensus using Cohen's {kappa}, accuracy, weighted F1, and per-call cost and latency. Results: Mean human inter-rater agreement was {kappa} = 0.79 (substantial). Both LLMs exceeded this baseline (cost-optimized {kappa} = 0.85; flagship {kappa} = 0.85) with nearly identical accuracy (0.92) and weighted F1 (0.93 vs. 0.93). Performance was strong on positive (F1 ~ 0.97) and negative (F1 ~ 0.90) classes but poor on the underrepresented neutral class (F1

15.
arXiv (quant-ph) 2026-06-11

Polarization-Resolved Photon Statistics of Cavity Quantum Materials

arXiv:2606.11550v1 Announce Type: cross Abstract: By forming hybrid light-matter states, optical cavities offer a route for engineering material properties, however, unambiguously probing the effects of light-matter coupling remains difficult. Here, we show that the polarization-resolved statistics of photons transmitted through a cavity, measurable via $g^{(2)}$, provide one such diagnostic. By relating $g^{(2)}$ to matter correlation functions such as the Raman structure factor, we link photon bunching and antibunching to material properties. By applying this method to the stripy-to-antiferromagnetic transition in the Kitaev-Heisenberg spin model, we find that polarization-dependent patterns of bunching and antibunching encode the magnetic point-group symmetries of each phase and characterize the behavior at the phase boundary. Finally, we predict measuring $g^{(2)}$ for output photon pairs polarized orthogonal to the input field will isolate higher-order light-matter scattering processes that probe higher-order material correlations.

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

Goal2Pixel: Grounding Goals to Pixels for Vision-Language Navigation

Vision-language models (VLMs) have become a common foundation for vision-and-language navigation in continuous environments (VLN-CE). Yet most VLM-based methods cast navigation as low-level action prediction, an interface that is ambiguous, tied to short-horizon motion primitives, and inefficient due to repeated VLM querying. We propose Goal2Pixel, a pure pixel-based paradigm that reformulates VLN-CE as navigable pixel grounding. Rather than predicting actions, Goal2Pixel uses the image plane as a unified spatial interface between VLM reasoning and robot motion: the model predicts a visible navigable pixel to the agent, which is back-projected into a 3D waypoint for forward navigation. For non-forward actions, we append auxiliary directive regions to the image plane, where the left/right/bottom regions are interpreted as turning left, turning right, and stopping, respectively. To enable long-horizon navigation, we propose a visibility-aware keyframe memory for compact and informative history representation. To adapt pretrained VLMs to navigable pixel grounding, we introduce semantic embeddings and coordinate-aware auxiliary losses. Goal2Pixel achieves competitive state-of-the-art performance while requiring fewer VLM inference calls than prior methods. On R2R-CE Val-Unseen it achieves 54.1% SR and 52.5% SPL with just 7.75 VLM calls per episode, 6x fewer than the 46.62 required by direct action prediction at 32.9% SR. The same trend holds on RxR-CE.Project Page: https://baobao0926.github.io/Goal2Pixel/.

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

Automatic ply-specific analyses of CFRP micrographs using shortest-path-based ply distinction

We present an automated approach to distinguish between ply instances in semantic segmentation masks of high-resolution carbon-fiber reinforced polymer micrographs. Interpreting the segmentation mask as a graph with pixels as vertices, enables us to use a shortest-path algorithm yielding the ply-separating paths. Thereby, we bridge the gap between semantic segmentation and ply instance segmentation using global information. We successfully apply our approach on high-resolution micrographs featuring a broad range of characteristics like artificially added gaps in single or multiple plies, different stacking sequences and ply traversing cracks. Assigning each fiber pixel to a ply based on the calculated paths, allows for a comprehensive, quantitative ply analysis with respect to its microstructural properties like the local fiber volume fraction as well as locally resolved ply and interleaf layer thickness. These insights help to reveal manufacturing-induced inhomogeneities, draw conclusions on manufacturing parameters and link mechanical properties to underlying microstructural imperfections.

18.
arXiv (CS.CL) 2026-06-15

Reward-SQL: Boosting Text-to-SQL via Stepwise Execution-Aware Reasoning and Process-Supervised Rewards

Recent advances in large language models (LLMs) trained with reinforcement learning (RL) have improved Text-to-SQL performance. However, RL-based approaches still struggle with complex queries due to two key limitations: insufficient stepwise execution-aware reasoning grounded in database feedback, and the lack of process-level rewards for guiding reasoning optimization. To address these issues, we propose CoCTE, a divide-and-conquer and execution-aware reasoning framework that progressively composes SQL queries through intermediate view validation and structured Common Table Expressions (CTEs), improving both accuracy and interpretability. To realize a CoCTE reasoning process, we develop Reward-SQL, a unified approach with three stages: (1) model initialization, which equips LLMs with structured CoCTE reasoning capabilities; (2) process reward design, which delivers fine-grained, execution-aware supervision; and (3) process-supervised RL and inference, which integrates process rewards into training and guides the inference stage by process rewards. This paper addresses the core challenges in Reward-SQL and makes the following contributions. We introduce a process reward model (PRM) that combines execution-aware trajectory scoring with entropy-based step weighting, providing dense and interpretable supervision across reasoning steps. We integrate PRM into both RL training and inference stages, stabilizing optimization and improving trajectory exploration with process-level signals. Experiments show that Reward-SQL significantly outperforms baselines with comparable model sizes, and exhibits strong cross-domain generalization.

19.
arXiv (CS.CL) 2026-06-16

Understanding the Behaviors of Environment-aware Information Retrieval

Recent retrieval-augmented generation (RAG) approaches have demonstrated strong capability in handling complex queries, yet current research overlooks a critical challenge: different retrievers require fundamentally different query formulation strategies for optimal performance. In this work, we present the first systematic analysis of how LLMs can learn to adapt their query formulation strategies for different retrievers via reinforcement learning (RL). Our empirical study reveals that RL effectively teaches an LLM to tailor its queries to specific retriever characteristics. We discover that different retrievers exhibit surprisingly distinct optimal query styles (e.g., descriptive vs. question-like), suggesting strategies learned for one retriever ineffective for another. We further show that performance can be enhanced by incorporating retriever-specific human guidance and by scaling model size. To facilitate learning over multi-retrieval-step trajectories, we introduce a branching-based rollout technique that improves training stability. Our work provides the first empirical evidence and actionable insights for building truly retriever-aware RAG systems. Code and resources are available at https://github.com/LCO-Embedding/Envs-aware-Information-Retrieval.

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

Code Correctness Signals in LLM Hidden States: Pre-Generation Probing and Repair Geometry

arXiv:2606.14530v1 Announce Type: new Abstract: Large language models encode rich information in their hidden states. This work asks whether code correctness is legible in the hidden states of Qwen3-4B-Instruct-2507, before it generates and as it repairs a failed attempt, studied on 444 LiveCodeBench tasks. It reports two findings connected by a single confound-control tool: residualization. First, the correctness of the model's first-attempt code is linearly decodable from the prompt-final hidden state, with a leakage-free held-out AUC of 0.931 +/- 0.008 across 50 outer splits. After the linear effect of prompt length is removed from each hidden state dimension, the probe still reaches 0.911 +/- 0.010, well above a prompt-length baseline of 0.754 +/- 0.014. Second, on 236 cleaned cases where the model attempts to repair a failed first attempt, the hidden state shift from the failing attempt to its repair carries a statistically detectable contrastive direction, significant on both a magnitude and a split-half test against label-shuffled nulls. This direction does not survive a conditional residualization against repair-context covariates that differ between successful and failed repairs, marking it as a correlate of repair success driven by the repair context rather than an isolated repair-comprehension feature. The probe layer is selected by nested cross-validation, and the same residualization approach that upholds the pre-generation correctness result overturns the repair-direction interpretation. The contribution is as much methodological as empirical: a diagnostic honest enough to report a negative result alongside a positive one.

21.
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.

22.
Nature (Science) 2026-06-10

The Amazon can be saved — with concerted action inside and outside Brazil

作者: 未知作者

As deforestation in the Amazon falls, fresh evidence shows that the rainforest can withstand global warming, but only if there is a worldwide effort to stop cutting it down. As deforestation in the Amazon falls, fresh evidence shows that the rainforest can withstand global warming, but only if there is a worldwide effort to stop cutting it down.

23.
medRxiv (Medicine) 2026-06-15

Two Blood-based Endotypes Reveal Divergent Clinical Outcomes of Fibrotic Hypersensitivity Pneumonitis

Rationale: Fibrotic hypersensitivity pneumonitis (fHP) is an antigen-driven, life-threatening interstitial lung disease characterized by heterogeneous radiologic features, clinical outcomes, and treatment responses. Objectives: To identify blood-based fHP endotypes that inform mechanism, prognosis and therapeutic response. Methods: We performed integrative analyses of multi-compartment transcriptomic data derived from whole blood, peripheral blood mononuclear cells, bronchoalveolar lavage, and surgical lung biopsies, alongside circulating plasma proteomics. Multiple clustering algorithms were cross-compared to ensure robustness and reproducibility of endotypes identification. Immune cell composition was inferred using bulk RNA-seq deconvolution and annotated with BAL single-cell RNA-seq. Pathway activities were characterized using Gene Set Enrichment Analysis. Transplant-free survival (TFS) was evaluated for endotype and corticosteroid exposure by Kaplan-Meier methods, with hazard ratios analyzed using multivariable Cox proportional hazards models. Results: Two molecular endotypes, lymphocytic-associated (L-fHP) and non-lymphocytic-associated (N-fHP), were identified and validated. L-fHP showed enrichment of adaptive immune signaling and lymphocyte predominance, whereas N-fHP demonstrated myeloid-cell activation with neutrophil and macrophage predominance. Corticosteroid exposure was associated with worse TFS in L-fHP but not in N-fHP after adjusting for age, sex, and baseline pulmonary function. Compared to L-fHP, N-fHP had poorer baseline pulmonary function, faster 12-month FVC decline, and shorter TFS. N-fHP also exhibited elevated neutrophil-associated markers, including matrix metalloproteinase-9, across paired transcriptomic and proteomic datasets, supporting a neutrophil-driven, cross-compartment disease process. Conclusion: Multi-omic, multi-compartment analysis identifies two reproducible fHP endotypes with distinct clinical outcomes and corticosteroid responses, supporting a precision medicine approach beyond current clinical and radiologic classification.

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

Physics-Aware Auxiliary Losses Improve Out-of-Distribution Generalization of a GNN Synthesizability Filter

arXiv:2606.12651v1 Announce Type: new Abstract: Machine-learning drug-discovery pipelines increasingly rely on generative models that propose molecules far from the data used to train downstream synthesizability filters. Existing filters (SAScore, SCScore, RAscore, DeepSA) are purely statistical and degrade in exactly this out-of-distribution (OOD) regime. We ask whether cheap, closed-form physical priors, used as auxiliary supervision on a graph neural network (GNN), improve OOD generalization. We add two auxiliary losses to a GINE backbone: a topological complexity regression supervised by the Bertz index, and a strain-energy soft penalty supervised by MMFF94 force-field energy. On a 65,177-molecule corpus (HIV, Tox21, COCONUT) labeled by SAScore thresholds we reproduce a strong in-distribution baseline, then evaluate a 4-way ablation (baseline / +complexity / +strain / +both) on a single-source OOD split (train on drug-like HIV+Tox21, test on COCONUT natural products), repeated over 5 seeds with paired bootstrap confidence intervals. All three physics-aware variants give a small but statistically significant OOD improvement over the baseline (mean OOD AUC 0.9774): +complexity Delta = +0.0060 (95% CI [+0.0023, +0.0102]), +strain Delta = +0.0032 ([+0.0008, +0.0052]), +both Delta = +0.0066 ([+0.0038, +0.0093]); every interval excludes zero, and the combination is best. The variants are indistinguishable in-distribution, so the effect is visible only under OOD evaluation. We are explicit that the effects are modest, and we report a cautionary methodological finding: a single-seed version of this experiment produced a qualitatively different (non-monotone) story that did not survive multi-seed evaluation.

25.
arXiv (CS.LG) 2026-06-11

Spatially Masked Regression Reveals Local and Distributed Predictability in Electrophysiological Recordings

arXiv:2606.11415v1 Announce Type: cross Abstract: Neural recordings are often interpreted as local measurements, yet the signal at any one sensor can also reflect structured activity distributed across the broader network. This raises a basic question: to what extent does an electrode's signal reflect local versus distributed information in the underlying system? More specifically, how much of an electrode's activity is carried by its immediate neighborhood, and how much is embedded more broadly across the array? We address this with a Spatially Masked Regression (SMR) framework that reconstructs each electrode's timeseries from the remaining electrodes while excluding a configurable neighborhood around the target. By progressively increasing this mask, spatial locality becomes an experimental control for quantifying how much predictive information survives after nearby channels are withheld. We apply SMR to intracranial EEG with heterogeneous electrode coverage and to scalp EEG with standardized montages over sensorimotor cortex. Using distance correlation between original and reconstructed signals, we find strong within-subject reconstruction in both modalities, substantial residual predictability even when local neighbors are excluded, and markedly stronger cross-subject transfer in EEG than in iEEG. Masking shows that nearby electrodes contribute strongly to reconstruction but do not account for all of it, indicating that individual channels reflect both local redundancy and broader distributed structure. Surrogates that preserve selected marginal or spectral properties while disrupting phase structure or temporal ordering substantially reduce performance, supporting the conclusion that SMR depends on structured temporal and cross-channel organization rather than on marginal statistics alone. These results position SMR as an interpretable framework for quantifying the balance between local and distributed information in recordings.