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Received — 27 May 2026 ⏭

A Non-Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development

✇(Multiomics OR Omics) AND (Lung OR gastric OR Hepatocellular)
By: Qian Tang · Chen Lian · Xinyan Han · Xuhan Zhang · Zihan Wang · Boyu Wang · Taoyu Zhu · Xinrui Lin · Xiaolei Wang · Yaping Xu · Manyu Xiao · Zijin Wang · Junming Li · Silin Chen · Yunze Wang · Yufei Liu · Songsong Li · Zuolin Shen · Xi Lu · Xueqi Han · Yilu Zhou · Mingyang Xiao · Jiayi Ran · Xiaoran Cao · Xinyi Xu · Hugo Sámano-Sánchez · Alfredo Rodríguez · Lian Wang · Shuifang Chen · Zhanyu Xu · Shirong Zhang · Nuo Yang · Yong Tang · Jian Liu
26 May 2026 at 18:00

Adv Sci (Weinh). 2026 May 26:e75839. doi: 10.1002/advs.75839. Online ahead of print.

ABSTRACT

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

PMID:42189071 | DOI:10.1002/advs.75839

A Non-Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development

✇Omics In Lung
By: Qian Tang · Chen Lian · Xinyan Han · Xuhan Zhang · Zihan Wang · Boyu Wang · Taoyu Zhu · Xinrui Lin · Xiaolei Wang · Yaping Xu · Manyu Xiao · Zijin Wang · Junming Li · Silin Chen · Yunze Wang · Yufei Liu · Songsong Li · Zuolin Shen · Xi Lu · Xueqi Han · Yilu Zhou · Mingyang Xiao · Jiayi Ran · Xiaoran Cao · Xinyi Xu · Hugo Sámano-Sánchez · Alfredo Rodríguez · Lian Wang · Shuifang Chen · Zhanyu Xu · Shirong Zhang · Nuo Yang · Yong Tang · Jian Liu
26 May 2026 at 18:00

Adv Sci (Weinh). 2026 May 26:e75839. doi: 10.1002/advs.75839. Online ahead of print.

ABSTRACT

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

PMID:42189071 | DOI:10.1002/advs.75839

CITYREP: A Unified Benchmark for Urban Representations Across Cities, Tasks, and Modalities

✇cs.AI, q-bio.NC updates on arXiv.org
By: Junyuan Liu · Xinglei Wang · Zichao Zeng · Jiazhuang Feng · Quan Qin · Ilya Ilyankou · Guangsheng Dong · Tao Cheng
26 May 2026 at 12:00
arXiv:2605.26036v1 Announce Type: new Abstract: Urban representation learning encodes complex urban environments into general-purpose embeddings for diverse downstream tasks and emerging urban foundation models. However, current evaluations are limited, typically focusing on one or two cities and tasks and relying on random splits that introduce spatial leakage, leading to inflated performance and weak support for cross-location generalization and fair comparison. To address this, we propose CityRep, a unified benchmark that evaluates urban representations across data modalities, cities, and tasks using spatially structured splits. CityRep consists of three key components: (1) a spatial unit-agnostic evaluation framework that supports heterogeneous urban representations through a standardized alignment module; (2) a unified evaluation protocol using block-based spatial splits to mitigate spatial leakage and enable rigorous model comparison; and (3) an extensible multi-city, multi-task benchmark suite spanning 8 cities and 8 tasks across regression, classification, and distribution prediction. We evaluate 11 representative urban representation models. Results show that performance is highly sensitive to the split protocol, with random splits inflating scores and altering model rankings. We also observe substantial variability across cities and tasks, underscoring the need for generalization-aware evaluation. CityRep is released as a reproducible benchmark with datasets, evaluation pipelines, and diagnostic tools to facilitate fair comparison and support future research in urban representation learning towards urban foundation models.

Uncertainty-DTW for Sequences and Visual Tokens

✇cs.AI, q-bio.NC updates on arXiv.org
By: Lei Wang · Syuan-Hao Li · Yongsheng Gao · Piotr Koniusz
26 May 2026 at 12:00
arXiv:2605.25110v1 Announce Type: cross Abstract: Aligning structured data is a fundamental problem in computer vision and machine learning, underlying tasks such as time series analysis, human action recognition, and visual representation learning. Existing alignment methods, including Dynamic Time Warping (DTW) and its differentiable variants, rely on deterministic similarity measures and are therefore sensitive to heterogeneous and noisy features. In this work, we introduce uncertainty-aware alignment, a probabilistic framework that models pairwise correspondences with heteroscedastic uncertainty and performs structured matching along alignment paths. Our formulation, uncertainty-DTW (uDTW), assigns each correspondence a Normal distribution and parametrizes each alignment path by a Maximum Likelihood Estimate objective consisting of (i) a precision-weighted matching term that suppresses unreliable features, and (ii) a log-variance regularization that prevents degenerate solutions. This yields a probabilistic alignment mechanism that is robust to noise and interpretable, as uncertainty directly reflects the reliability of matches. We further generalize this framework from temporal sequences to tokenized visual representations, enabling structured matching over sets of visual tokens. The learned uncertainty can be interpreted as a reverse-attention: semantically relevant regions exhibit low uncertainty and dominate the alignment, while ambiguous/noisy regions have high uncertainty. This provides a connection between alignment, attention, and uncertainty modeling. We evaluate the proposed framework across diverse domains. The results demonstrate consistent improvements over state-of-the-art methods and show that learned uncertainty correlates with semantic importance. These findings establish uncertainty-aware alignment as a general, robust, and interpretable framework for learning from structured data.

Trust-Aware Joint Feature-Prediction Discrepancy for Robust Domain Adaptation

✇cs.AI, q-bio.NC updates on arXiv.org
By: Xi Ding · Lei Wang · Syuan-Hao Li · Yongsheng Gao
26 May 2026 at 12:00
arXiv:2605.25119v1 Announce Type: cross Abstract: Domain adaptation aims to mitigate performance degradation caused by distribution shifts between a labeled source domain and an unlabeled or sparsely labeled target domain. Most existing approaches estimate domain discrepancy either in feature space or in prediction space. However, these single-perspective strategies overlook a critical problem under domain shift: the reliability of the signals used for alignment. In practice, both learned representations and semantic predictions may become unreliable, and treating all target samples equally can lead to misleading alignment and suboptimal transfer. We introduce trust-aware domain adaptation, a principled framework that models domain discrepancy through the reliability of feature and prediction signals. Central to our approach is the Joint Feature-Prediction Discrepancy (JFPD), a unified formulation that jointly captures representation divergence and prediction divergence while weighting their contributions by sample-specific trust. Trust is quantified via two complementary mechanisms: uncertainty-aware trust, derived from prediction entropy to suppress unreliable predictions, and semantic-alignment trust, computed from prototype similarity in feature space to emphasize well-aligned representations. By prioritizing confident and semantically consistent samples while down-weighting noisy or ambiguous ones, JFPD provides a reliability-aware estimate of domain discrepancy. We further integrate JFPD into a training objective that guides adaptation toward trustworthy regions of the target domain. Experiments on standard benchmarks demonstrate that the proposed framework consistently achieves superior adaptation performance and yields discrepancy estimates that correlate with target-domain error. This work addresses, for the first time, the importance of modeling trust in the interaction between features and predictions for domain adaptation.

Test-Time Self-Adaptive Conditioning for Stable Audio-Driven Talking-Head Generation

✇cs.AI, q-bio.NC updates on arXiv.org
By: Zhicheng Zhang · Lei Wang · Yu Zhang · Yongsheng Gao
26 May 2026 at 12:00
arXiv:2605.25488v1 Announce Type: cross Abstract: Audio-driven talking-head generation has achieved remarkable progress with recent models such as AniTalker, FLOAT, and Sonic. Despite their success, most existing approaches rely on a single static reference image to condition the entire video generation process at inference stage. This static conditioning paradigm often creates a mismatch between fixed identity features and dynamically evolving facial motion, leading to identity drift, temporal inconsistency, and degraded perceptual quality. We introduce Test-Time Self-Adaptive Conditioning (TT-SAC), a parameter-free inference framework that enables pretrained talking-head generators to adapt their conditioning representations during inference without retraining, gradient updates, or additional supervision. Instead of treating the reference portrait as immutable, TT-SAC composes the generator with its encoder in a feedback loop: the generator's own outputs are re-encoded to construct a refined conditioning representation that better aligns with the temporal dynamics of the synthesized sequence. A single adaptation step approximates a self-consistent equilibrium of the generative process, stabilizing identity and motion across time. We further provide theoretical analysis showing that test-time conditioning adaptation reduces feature variance and improves generative stability under mild Lipschitz assumptions, while exhibiting a principled bias-variance tradeoff that governs the optimal strength of adaptation. Extensive experiments on state-of-the-art talking-head generators and benchmark datasets demonstrate consistent improvements in lip-sync accuracy, temporal coherence, identity preservation, and perceptual fidelity. TT-SAC offers a model-agnostic and training-free strategy for enhancing generative video models, establishing test-time conditioning adaptation as an effective mechanism for stabilizing audio-driven portrait animation.
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