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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

Received — 4 April 2026 ⏭

Hierarchical Memory Orchestration for Personalized Persistent Agents

✇cs.AI, q-bio.NC updates on arXiv.org
By: Junming Liu · Yifei Sun · Weihua Cheng · Haodong Lei · Yuqi Li · Yirong Chen · Ding Wang
3 April 2026 at 12:00
arXiv:2604.01670v1 Announce Type: new Abstract: While long-term memory is essential for intelligent agents to maintain consistent historical awareness, the accumulation of extensive interaction data often leads to performance bottlenecks. Naive storage expansion increases retrieval noise and computational latency, overwhelming the reasoning capacity of models deployed on constrained personal devices. To address this, we propose Hierarchical Memory Orchestration (HMO), a framework that organizes interaction history into a three-tiered directory driven by user-centric contextual relevance. Our system maintains a compact primary cache, coupling recent and pivotal memories with an evolving user profile to ensure agent reasoning remains aligned with individual behavioral traits. This primary cache is complemented by a high-priority secondary layer, both of which are managed within a global archive of the full interaction history. Crucially, the user persona dictates memory redistribution across this hierarchy, promoting records mapped to long-term patterns toward more active tiers while relegating less relevant information. This targeted orchestration surfaces historical knowledge precisely when needed while maintaining a lean and efficient active search space. Evaluations on multiple benchmarks achieve state-of-the-art performance. Real-world deployments in ecosystems like OpenClaw demonstrate that HMO significantly enhances agent fluidity and personalization.
Received — 11 March 2026 ⏭

Hit-RAG: Learning to Reason with Long Contexts via Preference Alignment

✇cs.AI, q-bio.NC updates on arXiv.org
By: Junming Liu · Yuqi Li · Shiping Wen · Zhigang Zeng · Tingwen Huang
10 March 2026 at 12:00
arXiv:2603.07023v1 Announce Type: cross Abstract: Despite the promise of Retrieval-Augmented Generation in grounding Multimodal Large Language Models with external knowledge, the transition to extensive contexts often leads to significant attention dilution and reasoning hallucinations. The surge in information density causes critical evidence to be submerged by voluminous noise, which complicates the discernment of relevant fragments within a dense input. In this paper, we propose \textbf{Hit-RAG}, a multi-stage preference alignment framework designed to resolve these cognitive bottlenecks through a progressive optimization pipeline. Our approach systematically refines the utilization of external evidence via three distinct stages. First, Supervised Fine-tuning establishes baseline context awareness to minimize information neglect. Next, Discriminative Preference Alignment enhances robustness against misleading distractors. Finally, Group-Relative Policy Optimization stabilizes logical synthesis to prevent reasoning collapse. Extensive evaluations on eight benchmarks demonstrate that Hit-RAG consistently yields substantial performance gains, enabling models to bridge the gap between context acquisition and accurate reasoning while surpassing much larger counterparts in long-context scenarios.
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