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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

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

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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

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

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Extracting Training Data from Diffusion Language Models via Infilling

✇cs.AI, q-bio.NC updates on arXiv.org
By: Yihan Wang · N. Asokan
arXiv:2605.24173v1 Announce Type: cross Abstract: Memorization in large language models has been studied almost exclusively through prefix-conditioned extraction, a natural choice for autoregressive models. However, diffusion language models (DLMs) can denoise masked tokens at arbitrary positions. Thus, prefix-only probing reveals only one facet of memorization in DLMs and significantly underestimates the risk of training-data extraction. In order to realistically model extractability of training data in DLMs, we introduce \emph{infilling extraction}, a data-extraction protocol parameterized by an arbitrary binary mask that subsumes prefix-only probing and accounts for the bidirectional inductive bias of DLMs. Instantiating it on LLaDA-8B and Dream-7B across five extraction modes, three training pipelines, and three corpora covering verbatim and partial leakage, we find that mask geometry governs extractability: edge-conditioned masks \emph{extract up to three times more} verbatim sequences than prefix-conditioned ones, and bidirectional access opens channels inaccessible in autoregressive models. In particular, we show that a realistic adversary with access to training data where personally identifiable information has been redacted, can even achieve higher recall on extracting redacted email addresses from DLMs than from scale-matched autoregressive models. Tunable parameters for decoding measurably affect extraction performance, while a follow-up supervised finetuning stage does not eliminate the prior memorization.
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Explainable Retinal Imaging for Prediction of Multi-Organ Dysfunction in Type 2 Diabetes

✇cs.AI, q-bio.NC updates on arXiv.org
By: Mini Han Wang · Liting Huang · Wei Hong · Boonthawan Wingwon
arXiv:2605.24912v1 Announce Type: cross Abstract: Background: Type 2 diabetes mellitus (T2DM) is increasingly recognised as a systemic disease characterised by coordinated dysfunction across metabolic, renal, lipid, and inflammatory pathways. Existing clinical assessments often fail to capture this multi-dimensional burden. Methods: We conducted a retrospective study of 1,195 patients using routinely collected laboratory biomarkers. System-level abnormality indices were constructed to quantify organ-specific dysfunction, and multi-system involvement was defined as abnormalities in two or more systems. Supervised machine learning models, including logistic regression, random forest, and gradient boosting, were trained to predict multi-system dysregulation. Model interpretability was achieved using SHapley Additive exPlanations (SHAP). Results: The gradient boosting model demonstrated near-perfect discrimination (AUC = 1.000), significantly outperforming logistic regression (AUC = 0.925). Feature attribution analysis revealed that hyperglycaemia, renal impairment, dyslipidaemia, and inflammation were the dominant drivers of multi-system risk. Dose-response relationships observed in partial dependence analyses further supported the biological plausibility of model predictions. Conclusion: This study presents an interpretable, data-driven framework for quantifying systemic disease burden in T2DM. By linking routine biomarkers to multi-organ dysfunction, our approach provides both predictive accuracy and mechanistic insight, offering potential for improved risk stratification and precision medicine in diabetes care. The data and code used in this study are openly available on GitHub at: https://github.com/MiniHanWang/Type-2-Diabetes-1.git
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Explainable Multi-Task Retinal Imaging Reveals Microvascular Signals for Systemic Risk Stratification in Type 2 Diabetes: A Pilot Study

✇cs.AI, q-bio.NC updates on arXiv.org
By: Mini Han Wang · Liting Huang · Wei Hong · Boonthawan Wingwon
arXiv:2605.24913v1 Announce Type: cross Abstract: Retinal imaging provides a non-invasive window into systemic microvascular health and has emerged as a potential biomarker for systemic diseases. However, whether retinal features encode biologically meaningful systemic signals that can be reliably interpreted using explainable artificial intelligence (XAI) remains unclear. An explainable multi-task deep learning framework was developed to investigate associations between retinal microvascular features and systemic abnormalities in Type 2 Diabetes Mellitus. A total of 11,011 fundus images from 2,719 individuals were analysed using a shared neural network with task-specific heads for glycaemic status, kidney abnormality, and multi-system involvement. Model interpretability was evaluated using Gradient-weighted Class Activation Mapping (Grad-CAM), anatomical masking, and vessel alignment analysis. The framework demonstrated task-dependent predictive performance, with the best discrimination observed for kidney abnormality (AUC up to 0.63), whereas glycaemic status prediction showed limited performance (AUC = 0.49-0.61). Explainability analyses consistently localized model attention to retinal vessels and peripapillary regions. Masking experiments showed that occlusion of vascular regions caused the greatest performance decline, indicating that retinal vessels were the primary predictive source. Different architectures exhibited heterogeneous attention patterns, suggesting multiple representational pathways for systemic signal encoding. This pilot study demonstrates that retinal microvascular features contain measurable signals associated with systemic abnormalities, particularly microvascular damage. By integrating multi-task learning with quantitative XAI validation, this framework advances retinal imaging toward interpretable digital biomarkers for systemic risk stratification in diabetes.
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Simulating Human Memory with Language Models

✇cs.AI, q-bio.NC updates on arXiv.org
By: Qihan Wang · Nicholas Tomlin · Michael Hu · Brian Dillon · Tal Linzen
arXiv:2605.25680v1 Announce Type: cross Abstract: Language models are increasingly being deployed as user simulators, but their memory is far more reliable than that of real users. To measure this gap, we run a series of classic memory experiments from psychology on both humans and language models. Across tasks, we find that out-of-the-box language models exhibit better memory than humans, even when prompted to imitate human behavior. We then show that better prompting strategies and the use of a compactor can cause language models to forget content in a more human-like way. Using these methods, we show preliminary evidence that language models with human-like memory constraints can function as more effective user simulators in a downstream education task. Finally, we release human reference data and benchmarks to support future work on simulating human memory with language models.
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Agent Primitives: Reusable Latent Building Blocks for Multi-Agent Systems

✇cs.AI, q-bio.NC updates on arXiv.org
By: Haibo Jin · Peng Kuang · Ye Yu · Xiaopeng Yuan · Haohan Wang
arXiv:2602.03695v2 Announce Type: replace-cross Abstract: While existing multi-agent systems (MAS) can handle complex problems by enabling collaboration among multiple agents, they are often highly task-specific, relying on manually crafted agent roles and interaction prompts, which leads to increased architectural complexity and limited reusability across tasks. Moreover, most MAS communicate primarily through natural language, making them vulnerable to error accumulation and instability in long-context, multi-stage interactions within internal agent histories. In this work, we propose \textbf{Agent Primitives}, a set of reusable latent building blocks for LLM-based MAS. Inspired by neural network design, where complex models are built from reusable components, we observe that many existing MAS architectures can be decomposed into a small number of recurring internal computation patterns. Based on this observation, we instantiate three primitives: Review, Voting and Selection, and Planning and Execution. All primitives communicate internally via key-value (KV) cache, which improves both robustness and efficiency by mitigating information degradation across multi-stage interactions. To enable automatic system construction, an Organizer agent selects and composes primitives for each query, guided by a lightweight knowledge pool of previously successful configurations, forming a primitive-based MAS. Experiments show that primitives-based MAS improve average accuracy by 12.0-16.5\% over single-agent baselines, reduce token usage and inference latency by approximately 3$\times$-4$\times$ compared to text-based MAS, while incurring only 1.3$\times$-1.6$\times$ overhead relative to single-agent inference and providing more stable performance across model backbones.
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Contextual Rollout Bandits for Reinforcement Learning with Verifiable Rewards

✇cs.AI, q-bio.NC updates on arXiv.org
By: Xiaodong Lu · Xiaohan Wang · Jiajun Chai · Guojun Yin · Wei Lin · Zhijun Chen · Yu Luo · Fuzhen Zhuang · Yikun Ban · Deqing Wang
arXiv:2602.08499v2 Announce Type: replace-cross Abstract: Reinforcement Learning with Verifiable Rewards (RLVR) is an effective paradigm for improving the reasoning capabilities of large language models. However, existing RLVR methods utilize rollouts in an indiscriminate and short-horizon manner: responses of heterogeneous quality within each prompt are treated uniformly, and historical rollouts are discarded after a single use. This leads to noisy supervision, poor sample efficiency, and suboptimal policy updates. We address these issues by formulating rollout scheduling in RLVR as a contextual bandit problem and proposing a unified neural scheduling framework that adaptively selects high-value rollouts throughout training. Each rollout is treated as an arm whose reward is defined by the induced performance gain between consecutive optimization steps. The resulting scheduler supports both noise-aware intra-group selection and adaptive global reuse of historical rollouts within a single principled framework. We provide theoretical justification by deriving sublinear regret bounds and showing that enlarging the rollout buffer improves the achievable performance upper bound. Experiments on six mathematical reasoning benchmarks demonstrate consistent gains in performance and training efficiency across multiple RLVR optimization methods.
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Multi-omics Analysis Reveals the Protection of a Quadruple Probiotic Mixture in Experimental Autoimmune Hepatitis

✇(Multiomics OR Omics) AND (Pancreatic)
By: Yu Chen · Shuhui Wang · Anzhuo Chen · Zhuoying Lin · Han Wang · Wanneng Li · Jun Liu · Jia Yao · Dean Tian · Yu Lei · Mei Liu

Probiotics Antimicrob Proteins. 2026 May 23. doi: 10.1007/s12602-026-11062-2. Online ahead of print.

ABSTRACT

Autoimmune hepatitis (AIH) is a chronic progressive inflammatory liver disease with a rising global incidence. The treatment of AIH remains challenging because first-line drugs show limited efficacy and systemic side effects. Gut microbiota plays a crucial role in the pathogenesis of AIH, leading to growing interest in developing probiotic-based therapies. In this study, we used multi-omics analysis to investigate the therapeutic effects of a quadruple probiotic mixture (Probiotic-quad) consisting of Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis, and Bacillus cereus in a well-established chronic AIH murine model. Our results showed that Probiotic-quad treatment significantly alleviated AIH progression, as evidenced by lower serum liver enzyme levels, ameliorated hepatic inflammatory infiltration and histopathological damage. Metagenomic sequencing results showed that gut dysbiosis in AIH mice was partially reversed after Probiotic-quad administration. Additionally, the integrity of the intestinal epithelial barrier was restored, accompanied by a reduction in serum lipopolysaccharide levels. Untargeted metabolomic and transcriptomic analysis revealed that Probiotic-quad treatment was linked to alterations in hepatic metabolism, including the citrate cycle and tryptophan metabolism, and was associated with reduced activation of the NF-κB and NOD-like receptor signaling pathways. These findings suggest that Probiotic-quad treatment ameliorates AIH severity and is potentially associated with changes in hepatic immune responses, metabolism, gut microbiota, and intestinal barrier function, highlighting its potential as an adjuvant therapy for AIH.

PMID:42176246 | DOI:10.1007/s12602-026-11062-2

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Ferroptosis and macrophage polarization: mechanisms, interplay, and implications for medical applications

✇Cell Death Discovery nature.com science feeds
By: Yajuan Zhao · Jianbin Fu · Ping Zhao · Yuan Jiang · Yuhan Wang · Yaopeng Zhang · Zhaorui Li · Yongjun Zhao · Niannian Li · Bao Lang · Yanhua Luo

Cell Death Discovery, Published online: 23 May 2026; doi:10.1038/s41420-026-03147-2

Ferroptosis and macrophage polarization: mechanisms, interplay, and implications for medical applications
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