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

Towards a future space-based, highly scalable AI infrastructure system design

arXiv:2511.19468v2 Announce Type: replace-cross Abstract: If AI is a foundational general-purpose technology, we should anticipate that demand for AI compute – and energy – will continue to grow. The Sun is by far the largest energy source in our solar system, and thus it warrants consideration how future AI infrastructure could most efficiently tap into that power. This work explores a scalable compute system for machine learning in space, using fleets of satellites equipped with solar arrays, inter-satellite links using free-space optics, and Google tensor processing unit (TPU) accelerator chips. To facilitate high-bandwidth, low-latency inter-satellite communication, the satellites would be flown in close proximity. We illustrate the basic approach to formation flight via an 81-satellite cluster of 1 km radius, and describe an approach for using high-precision ML-based models to control large-scale constellations. Trillium TPUs are radiation tested. They survive a total ionizing dose equivalent to a 5 year mission life without permanent failures, and are characterized for bit-flip errors. Launch costs are a critical part of overall system cost; a learning curve analysis suggests launch to low-Earth orbit (LEO) may reach $\lesssim$\$200/kg by the mid-2030s.

02.
arXiv (CS.CV) 2026-06-15

StereoGeo: an end-to-end stereo camera calibration method

In this work, we propose StereoGeo, an end-to-end network-based approach for stereo camera calibration. Our method estimates the focal lengths and gravity directions of the left and right cameras, as well as the relative extrinsic transformation relating them. Existing methods often rely on calibration patterns in structured environments or address only a single camera configuration, being limited to either intrinsic or extrinsic estimation, and depending on a multi-view setups. StereoGeo extends the GeoCalib algorithm, integrating deep neural network feature extraction with a differentiable optimizer. Extensive experiments on real-world benchmarks demonstrate that StereoGeo achieves competitive performance for intrinsic calibration and provides accurate stereo extrinsic estimation, outperforming existing methods that are limited to monocular settings. The dataset used in this work is partially publicly available at https://github.com/meddourimane/StereoGeo-dataset.

03.
arXiv (CS.CV) 2026-06-11

3D-CBM: A Framework for Concept-Based Interpretability in Generative 3D Modeling

This research introduces a framework for incorporating Concept Bottleneck Models (CBMs) into 3D generative architectures to address the inherent 'semantic gap' in deep geometric learning. As deep models become central to 3D content creation, explainability shifts from a peripheral feature to a fundamental requirement for trust and accountability in safety-critical domains such as healthcare and manufacturing. CBMs provide an intrinsic interpretability solution by constraining latent representations to align with human-defined concepts, yet their application to unstructured 3D data remains largely unexplored. We design, implement, and validate a formal 3D-CBM architecture that maps raw geometric inputs, including point clouds and meshes, into a multi-tiered taxonomy of interpretable primitives and functional attributes. The framework further identifies strategic datasets, such as PartNet and ShapeNet, specialized for concept-based supervision. Experimental results from a 3D part-manipulation proof-of-concept experiment demonstrate the framework's efficacy, achieving a concept prediction accuracy of 88.8\% and a Chamfer Distance of 0.0115. Critically, the model enables precise test-time intervention, allowing for the interactive correction of structural errors. This work establishes a foundation for semantically-steerable 3D generation and invites further exploration into collaborative human-in-the-loop design systems.

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

Teacher-Student Structure for Domain Adaptation in Ensemble Audio-Visual Video Deepfake Detection

The rapid advancement of generative AI models is leading to more realistic deepfake media, encompassing the manipulation of audio, video, or both. This raises severe privacy and societal concerns. Numerous studies in this area have yielded promising intra-domain results; however, these models frequently exhibit decreased efficacy when faced with data from dissimilar domains. Consequently, recent deepfake detection approaches focus on enhancing the generalization ability through multiple techniques that incorporate all input modalities, including audio, images, and their interactions. In this regard, we propose the EAV-DFD method, a generalized deep ensemble audio-visual model (EAV-DFD) combined with a domain adaptation mechanism utilizing a teacher-student framework to enhance the model's ability to perform and generalize effectively across unseen domains. To evaluate the model's performance, we used the FakeAVCeleb dataset as the primary domain and the DFDC, Deepfake_TIMIT, and PolyGlotFake datasets as an unseen domain. Our experimental results demonstrate that the proposed framework is efficient in domain adaptation, improving AUC performance of the model by 4.09%, 17.94%, and 0.5% on three unseen datasets, using only a small portion of them to train the student model. This leads to a novel deepfake detection model capable of adapting to new domains and interpreting which modality has been manipulated, highlighting the potential of our approach for real-world applications.

05.
arXiv (CS.CL) 2026-06-11

Vector Quantized Latent Concepts: A Scalable Alternative to Clustering-Based Concept Discovery

Large language models (LLMs) encode rich semantic information in their hidden states, yet it remains difficult to understand what information these internal representations capture. Latent concepts extracted from hidden states offer a promising direction for interpreting LLMs, but existing clustering-based methods face a trade-off: hierarchical clustering produces coherent concepts but is limited to small datasets due to its quadratic memory cost, while K-Means scales efficiently but may yield less semantically coherent concepts. We propose Vector Quantized Latent Concept (VQLC), a discrete concept learning framework that learns a codebook of latent concepts on frozen hidden states. Across 12 dataset-model settings, VQLC stays close to K-Means in computational cost, scales better than hierarchical clustering, and remains competitive in faithfulness, with the clearest gains on decoder-only models. LLMs-based evaluation, qualitative analysis, and a Sparse Autoencoder (SAE) comparison demonstrate that the learned concepts are interpretable and task-relevant.

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

Scene-Adaptive Nonlinear Tone Curves for Pseudo Ground-Truth Generation in Low-Light 3D Gaussian Splatting

Low-light novel view synthesis is challenging because dark multi-view images contain noise, weak structural detail, and compressed dynamic range. Recent 3D Gaussian Splatting (3DGS) methods address these challenges by generating pseudo ground-truth (pseudo-GT) images as supervision targets when paired normal-light references are unavailable. Existing pseudo-GT methods apply a uniform linear gain to all pixels, which clips bright regions while providing insufficient enhancement in dark regions, limiting reconstruction quality. We observe that nonlinear tone mappings, long established in 2D low-light enhancement, have not been explored for pseudo-GT generation in 3D reconstruction. Accordingly, we propose a scene-adaptive nonlinear tone-curve framework that replaces linear pseudo-GT with nonlinear alternatives. The framework introduces percentile-based normalisation for scene-agnostic curve application, a scene-adaptive offset for automatic black-level adjustment, and two complementary curves: Adaptive SoftExp (ASE), a bounded exponential curve, and Adaptive Poly3 (AP3), a data-driven cubic polynomial. The module changes only the pseudo-GT computation and leaves the 3DGS backbone unchanged. Experiments on three benchmarks covering 21 scenes show that both curves consistently outperform the linear baseline with PSNR improvements up to +4.34 dB on LOM and +3.25 dB on RealX3D. Both curves achieve similar performance despite their different mathematical forms, suggesting the improvement is curve-agnostic. Code is available at https://github.com/lvmingzhe/adaptiveToneCurve

07.
arXiv (CS.CV) 2026-06-24

EchoFoley: Event-Centric Hierarchical Control for Video Grounded Creative Sound Generation

Sound effects build an essential layer of multimodal storytelling, shaping the emotional atmosphere and the narrative semantics of videos. Despite recent advancement in video-text-to-audio (VT2A), the current formulation faces three key limitations: First, an imbalance between visual and textual conditioning that leads to visual dominance; Second, the absence of a concrete definition for fine-grained controllable generation; Third, weak instruction understanding and following, as existing datasets rely on brief categorical tags. To address these limitations, we introduce EchoFoley, a new task designed for video-grounded sound generation with both event level local control and hierarchical semantic control. Our symbolic representation for sounding events specifies when, what, and how each sound is produced within a video or instruction, enabling fine-grained controls like sound generation, insertion, and editing. To support this task, we construct EchoFoley-6k, a large-scale, expert-curated benchmark containing over 6,000 video-instruction-annotation triplets. Building upon this foundation, we propose EchoVidia a sounding-event-centric agentic generation framework with slow-fast thinking strategy. Experiments show that EchoVidia surpasses recent VT2A models by 40.7% in controllability and 12.5% in perceptual quality.

08.
arXiv (CS.CV) 2026-06-16

Attention-Based Prototype Calibration for Multi-Rater Few-Shot Medical Image Segmentation

Few-shot medical image segmentation methods typically assume a single ground-truth annotation, overlooking systematic variability across expert raters commonly observed in clinical datasets. We propose an attention-based prototype calibration framework for few-shot multi-rater segmentation that models rater-specific deviations from a consensus representation in prototype space. A lightweight yet principled attention operator directly refines rater prototypes without modifying the backbone feature extractor, making the approach fully compatible with existing prototype-based few-shot segmentation methods. This design preserves semantic consistency while enabling personalized segmentation outputs with minimal computational overhead. Experiments on multi-rater medical imaging datasets demonstrate consistent improvements over baseline prototype approaches, highlighting the effectiveness of structured prototype calibration for modeling annotation variability. Our code is available at https://github.com/truong2710-cyber/JAPC.

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

FACTR 2: Learning External Force Sensing for Commodity Robot Arms Improves Policy Learning

arXiv:2606.12406v1 Announce Type: cross Abstract: Contact-rich manipulation requires force sensitivity, but many robot arms lack dedicated force sensors due to their high cost. We present Neural External Torque Estimation (NEXT), a data-driven method that estimates external joint torques without needing any dedicated force sensors. NEXT trains in 1 minute from only 10 minutes of free-motion data, yet achieves estimates comparable to dedicated joint-torque sensors. NEXT enables force-feedback teleoperation on low-cost arms and improves policy learning through Force-Informed Re-Sampling Training (FIRST), which up-samples pre-contact and contact segments during behavior cloning. Across five long-horizon tasks, FIRST outperforms prior force-aware policies by over 17% in task progress. Together, NEXT and FIRST bring force-aware teleoperation and policy learning to off-the-shelf robots without additional sensing hardware. Video results and code are available at https://jasonjzliu.com/factr2

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

Distilling Examples into Task Instructions: Enhanced In-Context Learning for Real-World B2B Conversations

In-context learning (ICL) is the standard method for low-resource classification, yet its efficacy in specialized domains remains largely unexplored. We address the challenge of classifying semantically complex, multi-party B2B conversations, where traditional ICL encounters significant limitations, especially as context length increases due to the concatenation of multiple few-shot examples. We introduce the \texttt{Call Playbook} dataset, featuring five classification tasks derived from real-world B2B conversations targeting core sales concepts. To bridge the gap between performance and practical utility, we propose novel knowledge extraction methods that distill verbose examples into compact, interpretable representations of structured classification criteria and precise task descriptions. Our approach achieves a 99\% reduction in token usage and improves macro-averaged AUC by up to 7\% over traditional ICL. Notably, it remains robust as context grows, unlike advanced token compression baselines which degrade by over 9 F1 points. Importantly, our framework enables direct refinement of classification logic, addressing critical needs for transparency, efficiency, and user interaction in real-world NLP applications.

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

Vision Transformers for Face Recognition Need More Registers

Recent advances in Vision Transformers (ViTs) for face recognition (FR) have moved beyond the standard CLS-token paradigm. In this paradigm, a special classification token (CLS) is prepended to the patch embeddings and used as a representation of the input for downstream tasks. An alternative approach, Concatenated Patch Embeddings (CPE), instead leverages all patch tokens by concatenating them into a single vector, which is then projected into a compact face representation. CPE has been shown to improve recognition performance in comparison to CLS-based ones, but our qualitative analysis of attention maps showed the presence of artifacts that limit their interpretability. To address this issue, we incorporate register tokens, learnable tokens concatenated to the initial patch embeddings, and processed jointly through the ViT encoder blocks. This mechanism has been shown to produce more structured and interpretable attention maps compared to baseline ViT. We empirically demonstrate that these artifacts consistently appear across various ViT backbones, including small and large models, and that introducing register tokens effectively mitigates them. Adding four or eight registers significantly enhances interpretability, with eight registers providing the highest verification accuracies and smoothest attention structures. Our resulting model, ViT-8R, corresponds to a CPE-based ViT-B architecture augmented with eight register tokens achieves state-of-the-art performance among ViT-based FR models on large-scale IJB-B and IJB-C benchmarks. Also, ViT-8R produces substantially clearer attention maps compared with the baseline model, which offer deeper insight into the model's attention behavior (https://github.com/TaharChettaoui/ViT-FR-Registers)

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

PAWS: Preference Learning with Advantage-Weighted Segments

arXiv:2606.11982v1 Announce Type: new Abstract: Preference-based reinforcement learning (PbRL) learns policies from human trajectory-level comparisons, avoiding explicit reward design and expert demonstrations. Existing methods typically train utility functions on trajectory or segment-level preferences while relying on per-step utility estimates during policy optimization. This training and inference mismatch induces a distribution shift that severely degrades temporal credit assignment and limits policy learning. We analyze this issue and propose PAWS, a segment-based preference learning method that performs policy updates directly using segment-level advantage functions. By aligning utility training with policy optimization, PAWS preserves trajectory-level preference information and avoids unreliable per-step learning signals. Experiments on simulated robotic manipulation and locomotion tasks demonstrate that PAWS consistently outperforms existing PbRL approaches, highlighting the importance of distribution-consistent preference learning.

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

Leadership as Coordination Control: Behavioral Signatures and the Recovery-Advantage Boundary in Multi-Agent LLM Teams

作者:

Team science holds that leadership is contingent: it helps only under specific conditions, and capable, autonomous teams may need none at all. We ask the analogous question for multi-agent LLM teams: under what measurable conditions does process-level coordination control add value, and do those conditions match what team science predicts? We use behavioral signatures (majority lock-in, exploration, recovery from an incorrect round-0 consensus) and per-action ablations, clean because each controller is an explicit action set, not a monolithic prompt. We operationalize three classical leadership styles (transactional, transformational, situational) as controllers over a shared action vocabulary (explore, revise, accept, synthesize). A matched controller with the same actions but an arbitrary rule recovers no better than majority voting, so the theory-derived rule, not the vocabulary, does the work. Across four task regimes and three open-weight model families, no controller dominates by accuracy, as the contingency view predicts: transactional control matches a shared round-0 vote on all 12 (model, regime) combinations to within 1.3pp, and gains appear only on the one combination where the round-0 majority is unreliable (llama-4-scout social; situational +8pp over flat). A recovery-advantage account, tested with four boundary probes, says a controller beats plain interaction only where the round-0 majority is unreliable, the task is recoverable, and undirected interaction does not already repair it. These regions map onto contingency theory (leadership substitutes, path-goal redundancy, the situational readiness gap), so a largely null accuracy result is what the theory predicts, not a failure of the controllers. We read process-level coordination control as a contingency to be measured and theory-mapped, not a leaderboard to be topped.

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

Guiding Federated Graph Recommendation with LLM-encoded knowledge

arXiv:2606.15277v1 Announce Type: cross Abstract: Graph-based recommender systems are highly effective at extracting collaborative signals from user–item interactions, and federated learning (FL) allows these models to be trained while preserving user privacy. However, aggregating graph representations across distributed, non-IID clients remains a challenge; structural embeddings learned locally often misalign, and naive averaging fails to capture meaningful cross-client relationships. Most existing federated graph methods rely exclusively on structural aggregation, neglecting the rich, global semantic context available in large language models (LLMs). In this paper, we propose a novel framework that uses LLM-encoded knowledge to guide federated graph recommendation. Specifically, clients learn structural representations from local graphs while simultaneously summarizing their typical interaction patterns into compact semantic vectors via a frozen LLM. The central server then uses these LLM-encoded semantic signals to discover related preference patterns across clients, guiding the selective aggregation of their structural representations. This enables semantically informed cross-client collaboration without exposing raw data. Extensive experiments on standard benchmarks show that guiding structural alignment with LLM-encoded knowledge consistently improves recommendation accuracy over existing federated graph baselines.

16.
medRxiv (Medicine) 2026-06-19

Hyperleukocytosis and outcomes in pediatric B-cell acute lymphoblastic leukemia: A report from the REDIAL Consortium

Hyperleukocytosis (white blood cell [WBC] count >100 000/uL) at diagnosis is an important prognostic risk factor in pediatric acute lymphoblastic leukemia (ALL), though its significance with contemporary therapy is unclear. We analyzed 1 826 pediatric ALL patients from a multi-institution cohort to determine whether hyperleukocytosis independently predicts outcomes using multivariable Cox proportional hazard modeling. Hyperleukocytosis occurred in 211 patients (12%), with 121 having B-ALL, and showed no prognostic significance in T-ALL patients. In B-ALL, 5-year event-free survival (EFS) was 65% versus 89% for non-hyperleukocytosis patients, and overall survival (OS) was 78% versus 93%. After adjustment for age, cytogenetic risk, central nervous system disease status, and treatment site, hyperleukocytosis remained an independent predictor of end-of-induction minimal residual disease (MRD) positivity (odds ratio 2.53 [95% confidence interval [CI]: 1.71-3.94; p

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

TokenPilot: Cache-Efficient Context Management for LLM Agents

As LLM agents are deployed in long-horizon sessions, context accumulation drives up inference costs. Existing approaches utilize text pruning or dynamic memory eviction to minimize token footprints; however, their unconstrained sequence mutations alter layouts, introducing prefix mismatches and cache invalidation. This reveals a critical trade-off between text sparsity and prompt cache continuity. To address this, we present TokenPilot, a dual-granularity context management framework. Globally, Ingestion-Aware Compaction acts as a framework harness to stabilize prompt prefixes and eliminate open-world environmental noise at the ingestion gate. Locally, Lifecycle-Aware Eviction monitors the ongoing residual utility of context segments, enforcing a conservative batch-turn schedule to offload content segments only when task relevance expires. Experiments on PinchBench and Claw-Eval under both isolated and continuous modes demonstrate that TokenPilot reduces costs by 61% and 56% in isolated mode, and 61% and 87% in continuous mode, while maintaining competitive performance compared to prior systems. TokenPilot has been integrated into LightMem2 at https://github.com/zjunlp/LightMem2.

18.
Nature Medicine 2026-06-15

Blood signatures of cell type-specific aging forecast disease risk and resilience

作者: 未知作者

By measuring thousands of proteins in blood samples from over 60,000 people, we built molecular ‘clocks’ to estimate how fast cells age. Our analyses show that cell types age at different rates within the same person. Accelerated aging of specific cell types is associated with increased disease risk, whereas slower aging of others is linked to protection and improved survival.

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

Bounding Box Label Propagation for Re-Annotation of Document Layout Analysis Datasets

Datasets in practical document processing scenarios typically grow over time, and their class annotations undergo continuous refinement. This creates significant re-annotation efforts, which are time-consuming and costly. A promising remedy is to re-annotate only a small subset of available documents manually and apply semi-supervised learning techniques that leverage both labelled and unlabelled data. Although there are numerous approaches to tackle this problem for classification, there exists no adaptation for the problem of re-classifying object detection instances, e.g. for document layout analysis. To this end, we propose Bounding Box Label Propagation (BBLP), a pseudo-labelling framework for object detection. An object encoder integrates visual, textual, and positional embeddings from object detection samples to come up with a joint embedding that can be used for Label Propagation on partially annotated datasets in a plug-and-play fashion. Evaluation results indicate that the proposed approach produces high-quality class annotations of bounding boxes. In the D4LA layout analysis dataset, it achieves a mAP of 54.0%, corresponding to 81.6% of fully supervised performance, while using only 10% labelled data. Our work demonstrates the potential of Label Propagation for object detection and lays the groundwork for reducing manual annotation efforts in real-world document processing applications.

20.
arXiv (CS.CV) 2026-06-16

Learning Fine-Grained Correspondence with Cross-Perspective Perception for Open-Vocabulary 6D Object Pose Estimation

Open-vocabulary 6D object pose estimation empowers robots to manipulate arbitrary unseen objects guided solely by natural language. However, a critical limitation of existing approaches is their reliance on unconstrained global matching strategies. In open-world scenarios, trying to match anchor features against the entire query image space introduces excessive ambiguity, as target features are easily confused with background distractors. To resolve this, we propose Fine-grained Correspondence Pose Estimation (FiCoP), a framework that transitions from noise-prone global matching to spatially-constrained patch-level correspondence. To systematically eliminate background interference, FiCoP first employs an object-centric disentanglement step to isolate the target from macro-level environmental noise. Building upon this localized region, our core methodological innovations are twofold. Firstly, a Cross-Perspective Global Perception (CPGP) module is proposed to fuse dual-view features, establishing structural consensus through explicit context reasoning and text-guided semantic injection. Secondly, we design a Patch Correlation Predictor (PCP) that leverages a patch-to-patch correlation matrix as a structural prior. This generates a precise block-wise association map, acting as a spatial filter to enforce fine-grained, noise-resilient matching. Experiments on the REAL275 and Toyota-Light datasets demonstrate that FiCoP improves Average Recall by 8.0% and 6.1%, respectively, compared to the state-of-the-art method, highlighting its capability to deliver robust and generalized perception for robotic agents operating in complex, unconstrained open-world environments. The source code will be made publicly available at https://github.com/zjjqinyu/FiCoP.

21.
Nature (Science) 2026-06-10

Light slows down carbon nanotubes in water

Water-suspended carbon nanotubes move more slowly in green light, suggesting that excited electrons in the tubes couple to the water through ‘quantum friction’. Water-suspended carbon nanotubes move more slowly in green light, suggesting that excited electrons in the tubes couple to the water through ‘quantum friction’.

22.
arXiv (CS.AI) 2026-06-18

Caring Without Feeling: Affective Dynamics as the Control Layer of Human-AI Agent Collaboration

arXiv:2606.18259v1 Announce Type: cross Abstract: AI agents that plan, retain memory across sessions, invoke external tools and act with partial autonomy are transforming human–AI collaboration. Research on affective computing, simulated empathy in large language models, trust in automation and AI safety has illuminated important design principles, yet these literatures remain fragmented. No integrated account explains how affective cues operate within agentic collaboration – settings in which humans delegate, monitor and correct consequential tasks. This Review synthesises computational and interactional mechanisms of affective dynamics: the processes through which affective cues, emotion-like behaviour and perceived agent affect shape trust calibration, delegation decisions, error correction, dependence and governance. We trace how model-generated affective signals enter interaction loops that govern reliance, repair and oversight, and propose a framework that treats affect not as an internal property of AI but as a coordination layer through which humans and agents negotiate capability, uncertainty and responsibility. The framework provides a foundation for calibrated measurement, purposeful design and informed governance.

23.
arXiv (CS.LG) 2026-06-16

Multiscale Hypersonic Boundary Layer Reconstruction via Spectral Binning and Subdomain-wise Conditional Diffusion

arXiv:2606.15023v1 Announce Type: cross Abstract: We propose a multiscale probabilistic reconstruction framework for hypersonic Couette flow, where near-wall states are inferred from limited top-wall observations using conditional diffusion model. The boundary layer is divided into overlapping wall-normal subdomains, and a single height- and Mach-conditioned Elucidating Diffusion Model (EDM) is trained jointly for M=6,7,8 to sample velocity, density, pressure, and temperature fields conditioned on a top-wall boundary slice. A soft overlap inpainting strategy assembles subdomain predictions into full-volume reconstructions while maintaining inter-subdomain continuity and small-scale variability. To improve the spectral fidelity of the generated fields, we introduce a novel bounded binned spectral power (BSP) loss that preserves high-wavenumber content while remaining numerically stable across the diffusion noise schedule. Validation against direct numerical simulation data shows that the model recovers instantaneous structures, spectra, statistical profiles, correlations, and wall quantities across all training Mach numbers, while providing spatially structured uncertainty estimates. The reconstructed Mach-conditioned profiles also collapse under the Trettel-Larsson transformation, indicating consistency with compressibility scaling. These results establish the domain decomposed conditional diffusion model with a bounded binned spectral loss as an effective probabilistic surrogate for near-wall reconstruction in hypersonic wall-bounded turbulence.

24.
medRxiv (Medicine) 2026-06-22

Integration of lung tissue proteomics and genome-wide association data to identify lung cancer susceptibility proteins and potential drug targets

Background: Proteins directly impact disease development and act as drug targets. Therefore, we integrated genomic and lung tissue proteomics data to identify lung cancer susceptibility proteins, elucidating genetic mechanisms and candidate drug targets. Method: We profiled the proteome and genome in non-neoplastic lung tissue from 200 lung cancer patients. Using this data, we constructed genetic models to predict abundance across the proteome in lung tissue. We applied these models to genome-wide association study (GWAS) data from 55,174 lung cancer cases and 1,294,174 controls to evaluate their associations with the risk of lung cancer, overall and by major histological subtypes. Bayesian colocalization and Mendelian randomization (MR) analyses were used to prioritize putative causal proteins, which were cross-referenced with three main drug-protein databases to identify potential therapeutic targets. Results: We identified 29 proteins associated with lung cancer risk at a false discovery rate < 5%, including 25 for overall lung cancer, two (AQP3 and IL18) specifically for adenocarcinoma, and another two (HMGN2 and HLA-DMB) for squamous cell carcinoma. Of them, genes encoding 17 proteins reside at least 2Mb away from any known GWAS risk loci, including 14 for overall lung cancer (HYI, GPX1, GMPPB, DSP, HDDC2, MTCH2, SUOX, JMJD7, PDIA3, IL16, IQGAP1, SULT1A2, ARHGAP27, and TYMP) and three for subtypes (AQP3, IL18, and HMGN2). Among the 12 proteins located within the known risk loci, EPHX2, CLDN18, PSMD5, and CYP2S1 proteins showed an association independent of the proximal GWAS-identified lead variant. Colocalization and/or MR analysis suggested 11 potential causal proteins. Five of these candidate causal proteins (DSP, CLDN18, IQGAP1, IL18 and TYMP) are targeted by nine drugs already approved by the FDA or in phase III trials. Conclusion: Our study identified novel lung cancer susceptibility proteins and potential drug targets, offering valuable insights into lung cancer biology and future translational utilities.

25.
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.