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

Rethinking Federated Unlearning via the Lens of Memorization

cs.AI, q-bio.NC updates on arXiv.org

By: Jiaheng Wei · Yanjun Zhang · He Zhang · Leo Yu Zhang · Chao Chen · Kok-Leong Ong · Jun Zhang · Yang Xiang

26 May 2026 at 12:00

arXiv:2605.24545v1 Announce Type: cross Abstract: Federated learning (FL) increasingly needs machine unlearning to comply with privacy regulations. However, existing federated unlearning approaches may overlook the overlapping information between the unlearning and remaining data, leading to ineffective unlearning and unfairness between clients. In this work, we revisit federated unlearning through the lens of memorization. We argue that unlearning should mainly remove the unique memorized information attributable to the data to be forgotten, while preserving overlapping patterns that are also supported by the remaining data. Specifically, we propose Grouped Memorization Evaluation, an example-level metric that separates memorized knowledge from overlapping knowledge. Building on this metric, we introduce Federated Memorization Pruning (FedMemPrune), a pruning-based unlearning approach that resets redundant parameters responsible for memorization. Extensive experiments show that FedMemPrune closely matches retraining-based unlearning baselines while more effectively eliminating memorization than existing federated unlearning algorithms, yielding strong unlearning performance without sacrificing the utility of retained knowledge.

OrpQuant: Geometric Orthogonal Residual Projection for Multiplier-Free Power-of-Two Transformer Quantization

cs.AI, q-bio.NC updates on arXiv.org

By: Maoyang Xiang · Bo Wang · Tao Luo

26 May 2026 at 12:00

arXiv:2605.26092v1 Announce Type: cross Abstract: The deployment of Large Language Models (LLMs) and Vision Transformers (ViTs) on edge devices is significantly constrained by memory limitations and the critical timing bottlenecks introduced by dense Multiply-Accumulate (MAC) arrays. In the ultra-low bit regime, logarithmic Power-of-Two (PoT) quantization provides a hardware-efficient alternative by replacing MAC operations with bit-shifts. However, the non-uniform exponential lattice is inherently limited by a \textbf{Low Angular Resolution Regime}, a structural flaw that becomes particularly pronounced at sub-4-bit thresholds, leading to a notable degradation of high-dimensional feature manifolds. To address this geometric limitation, we propose Orthogonal Residual Projection (ORP), an algorithm-hardware co-design framework. By formulating quantization as a dual-basis geometric projection, ORP adaptively synthesizes a higher-resolution residual lattice using strictly shift-and-add operations. Furthermore, ORP's analytical solver offers a practical alternative to computationally intensive gradient-based optimization, reducing the full-model calibration time for LLaMA-2-7B to approximately \textbf{15 minutes}. Extensive evaluations demonstrate ORP's applicability across modalities and its hardware efficiency. Under the 3-bit (W3/A16) constraint, ORP achieves a perplexity of 6.10 on LLaMA-2-7B, comparing favorably to conventional MAC-intensive baselines like AWQ without relying on asymmetric scaling, while maintaining competitive accuracy in 4-bit scenarios. At the silicon level, standard-cell RTL synthesis at a 28nm node indicates that ORP effectively mitigates the timing bottlenecks associated with dense multiplier trees.

Decoding ML Decision: An Agentic Reasoning Framework for Large-Scale Ranking System

cs.AI, q-bio.NC updates on arXiv.org

By: Longfei Yun · Yihan Wu · Haoran Liu · Xiaoxuan Liu · Ziyun Xu · Yi Wang · Yang Xia · Pengfei Wang · Mingze Gao · Yunxiang Wang · Changfan Chen · Wenjie Fu · Hong Yan · Junfeng Pan

26 May 2026 at 12:00

arXiv:2602.18640v2 Announce Type: replace Abstract: Modern large-scale ranking systems operate within a sophisticated landscape of competing objectives, operational constraints, and evolving product requirements. Progress in this domain is increasingly bottlenecked by the engineering context constraint: the arduous process of translating ambiguous product intent into reasonable, executable, verifiable hypotheses, rather than by modeling techniques alone. We present GEARS (Generative Engine for Agentic Ranking Systems), a framework that reframes ranking optimization as an autonomous discovery process within a programmable experimentation environment. Rather than treating optimization as static model selection, GEARS leverages Specialized Agent Skills to encapsulate ranking expert knowledge into reusable reasoning capabilities, enabling operators to steer systems via high-level intent vibe personalization. Furthermore, to ensure production reliability, the framework incorporates validation hooks to enforce statistical robustness and filter out brittle policies that overfit short-term signals. Experimental validation across diverse product surfaces demonstrates that GEARS consistently identifies superior, near-Pareto-efficient policies by synergizing algorithmic signals with deep ranking context while maintaining rigorous deployment stability.

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