❌

Normal view

Restoring circadian rhythms in the hypothalamic paraventricular nucleus reverses aging biomarkers and extends lifespan in male mice

Enhancing circadian amplitude in mouse hypothalamic paraventricular nucleus neurons by 3′-deoxyadenosine treatment alleviates age-related pathologies and extends lifespan.

Multi-Omics Characterization of Lactate-Associated Molecular Subtypes in Lung Cancer Suggests a Role for DKK1 in Lactate-Linked Migration, Invasion, and Lactylation Programs

Cancers (Basel). 2026 Feb 25;18(5):735. doi: 10.3390/cancers18050735.

ABSTRACT

BACKGROUND: Lactate accumulation is increasingly recognized as a feature of tumor metabolic reprogramming that can coincide with immune dysregulation and aggressive phenotypes. The prognostic and immunologic relevance of lactate-associated heterogeneity in lung cancer remains to be clarified.

METHODS: We curated lactate-related genes and identified prognostic candidates in lung cancer cohorts. Consensus clustering was applied to define lactate-associated molecular subtypes, followed by characterization of survival and tumor microenvironment features. A LASSO-based gene signature was developed to generate an individual-level risk score and an integrated nomogram. Multi-omics analyses were used to evaluate concordance between transcriptomic and proteomic alterations. Single-cell transcriptomic data were analyzed to explore cellular heterogeneity in lactate-related programs. In vitro assays evaluated the response of candidate genes to lactate exposure and assessed cell migration and invasion under proliferation-inhibited conditions after genetic perturbation.

RESULTS: Two lactate-associated molecular subtypes were identified with distinct overall survival and divergent immune microenvironment features. Subtype 1 was associated with better outcomes and a more immune-inflamed profile, whereas Subtype 2 was associated with poorer outcomes and a myeloid-enriched, immunosuppressive contexture. Pathway analyses indicated subtype-associated differences in extracellular matrix-related processes and apoptosis-associated signaling. We developed an 11-gene prognostic signature and nomogram that stratified patients by risk across TCGA and GEO cohorts. Multi-omics integration highlighted ANLN, FGA, and DKK1 as consistently dysregulated at both transcript and protein levels. Among these candidates, DKK1 showed lactate-responsive induction in vitro. DKK1 perturbation altered lactate-enhanced migratory and invasive phenotypes and was accompanied by changes in intracellular lactate levels and global protein lactylation, supporting a potential feedforward relationship between lactate exposure, DKK1 expression, and lactylation.

CONCLUSIONS: This study characterizes lactate-associated molecular heterogeneity in lung cancer and provides a lactate-related subtype framework and prognostic risk model for patient stratification. The findings nominate DKK1 as a lactate-responsive candidate linked to migration/invasion phenotypes and lactate/lactylation changes in vitro.

PMID:41827671 | PMC:PMC12985219 | DOI:10.3390/cancers18050735

Multi-Omics Characterization of Lactate-Associated Molecular Subtypes in Lung Cancer Suggests a Role for DKK1 in Lactate-Linked Migration, Invasion, and Lactylation Programs

Cancers (Basel). 2026 Feb 25;18(5):735. doi: 10.3390/cancers18050735.

ABSTRACT

BACKGROUND: Lactate accumulation is increasingly recognized as a feature of tumor metabolic reprogramming that can coincide with immune dysregulation and aggressive phenotypes. The prognostic and immunologic relevance of lactate-associated heterogeneity in lung cancer remains to be clarified.

METHODS: We curated lactate-related genes and identified prognostic candidates in lung cancer cohorts. Consensus clustering was applied to define lactate-associated molecular subtypes, followed by characterization of survival and tumor microenvironment features. A LASSO-based gene signature was developed to generate an individual-level risk score and an integrated nomogram. Multi-omics analyses were used to evaluate concordance between transcriptomic and proteomic alterations. Single-cell transcriptomic data were analyzed to explore cellular heterogeneity in lactate-related programs. In vitro assays evaluated the response of candidate genes to lactate exposure and assessed cell migration and invasion under proliferation-inhibited conditions after genetic perturbation.

RESULTS: Two lactate-associated molecular subtypes were identified with distinct overall survival and divergent immune microenvironment features. Subtype 1 was associated with better outcomes and a more immune-inflamed profile, whereas Subtype 2 was associated with poorer outcomes and a myeloid-enriched, immunosuppressive contexture. Pathway analyses indicated subtype-associated differences in extracellular matrix-related processes and apoptosis-associated signaling. We developed an 11-gene prognostic signature and nomogram that stratified patients by risk across TCGA and GEO cohorts. Multi-omics integration highlighted ANLN, FGA, and DKK1 as consistently dysregulated at both transcript and protein levels. Among these candidates, DKK1 showed lactate-responsive induction in vitro. DKK1 perturbation altered lactate-enhanced migratory and invasive phenotypes and was accompanied by changes in intracellular lactate levels and global protein lactylation, supporting a potential feedforward relationship between lactate exposure, DKK1 expression, and lactylation.

CONCLUSIONS: This study characterizes lactate-associated molecular heterogeneity in lung cancer and provides a lactate-related subtype framework and prognostic risk model for patient stratification. The findings nominate DKK1 as a lactate-responsive candidate linked to migration/invasion phenotypes and lactate/lactylation changes in vitro.

PMID:41827671 | PMC:PMC12985219 | DOI:10.3390/cancers18050735

Multi-omics investigation of benzo[a]pyrene in gastric cancer: comprehensive network toxicology, machine learning and molecular docking approaches

12 March 2026 at 18:00

Mol Divers. 2026 Mar 12. doi: 10.1007/s11030-026-11508-3. Online ahead of print.

ABSTRACT

Gastric cancer (GC) risk is shaped by environmental exposures such as benzo[a]pyrene (BaP). Here, we systematically identified BaP-toxicological targets and dissected their contribution to GC development. BaP-related targets were independently predicted with stringent filters from ChEMBL, Similarity Ensemble Approach (SEA) and PharmMapper databases, while GC-related targets were mined from the Comparative Toxicogenomics Database (CTD), GeneCards and OMIM databases. Overlapping targets were subjected to protein-protein interaction (PPI) network construction, functional enrichment analysis and molecular docking. We then integrated multi-omics data using ten clustering algorithms to identify the consensus GC subtypes, which were subsequently employed 101 machine learning combinations to develop a consensus benzo[a]pyrene-related signature (CBRS) for GC patients. As a result, we identified seven hub toxicological targets: ALB, HSP90AA1, ESR1, INS, TP53, TNF, and EGFR, underscoring their potential central roles in BaP-driven GC pathogenesis. These targets are enriched in the MAPK, Lipid and atherosclerosis, and PI3K-Akt signaling pathway. The BaP-toxicological classifiers and the CBRS prognostic model could provide useful support for risk stratification and inform personalized therapeutic strategies for GC patients. Molecular docking results suggest that BaP exhibits relatively strong binding affinity with these key toxicological targets, potentially implicating their involvement in BaP-induced gastric cancer toxicity. Therefore, this study integrates multi-dimensional omics data with advanced machine learning algorithms to establish a comprehensive analytical framework for the toxicological effects of between BaP and GC, which transcends the limitations of traditional analyses and offers unprecedented insights and evidence chains for elucidating the pathogenesis of GC.

PMID:41817952 | DOI:10.1007/s11030-026-11508-3

CSF1R T567M mutation induces microglial dysfunction and synaptic impairment in patient iPSC-derived cerebral organoids of CSF1R-related disorder

Cell Death Discovery, Published online: 12 March 2026; doi:10.1038/s41420-026-02995-2

CSF1R T567M mutation induces microglial dysfunction and synaptic impairment in patient iPSC-derived cerebral organoids of CSF1R-related disorder

Regulatory mechanisms of ALKBH5/CIITA axis in the synergistic modulation of hepatocellular carcinoma radiotherapy and immunotherapy

Genes Immun. 2026 Mar 10. doi: 10.1038/s41435-026-00382-6. Online ahead of print.

ABSTRACT

The prognosis for hepatocellular carcinoma remains grim. Combining radiotherapy with immune checkpoint blockade (ICB) has shown potential to enhance therapeutic outcomes, yet there is a pressing need for further advancements. Our previous research demonstrated that this combined approach suppresses ALKBH5 gene expression and increases m6A modification levels in hepatocellular carcinoma tissues. High-throughput sequencing and detailed molecular analysis revealed that inhibiting ALKBH5 amplifies CIITA m6A modifications post-therapy. This modulation triggers MHC II molecule expression in tumors, facilitating the presentation of tumor-associated antigens to CD4 + T lymphocytes and the recruitment of CD8 + T cells for an anti-tumor immune response. Building on these findings, we engineered a CIITA vector with a specific site mutation to confirm that the regulation of CIITA by the combined radiotherapy and immunotherapy is mediated through m6A methylation. Consequently, we established a comprehensive network involving ALKBH5, CIITA, MHC II, and CD4+ and CD8 + T cells. To elucidate the role and underlying molecular mechanisms of this combined therapy in reshaping the tumor immune microenvironment for hepatocellular carcinoma, we employed multi-omics approaches across in vitro, animal model, and clinical multi-dimensional studies, offering novel insights for enhancing treatment efficacy.

PMID:41807814 | DOI:10.1038/s41435-026-00382-6

Dexamethasone promotes neutrophil ROS-mediated tumor killing through the glucocorticoid receptor

Oncogene, Published online: 06 March 2026; doi:10.1038/s41388-026-03708-w

Dexamethasone promotes neutrophil ROS-mediated tumor killing through the glucocorticoid receptor

LifeBench: A Benchmark for Long-Horizon Multi-Source Memory

arXiv:2603.03781v1 Announce Type: new Abstract: Long-term memory is fundamental for personalized agents capable of accumulating knowledge, reasoning over user experiences, and adapting across time. However, existing memory benchmarks primarily target declarative memory, specifically semantic and episodic types, where all information is explicitly presented in dialogues. In contrast, real-world actions are also governed by non-declarative memory, including habitual and procedural types, and need to be inferred from diverse digital traces. To bridge this gap, we introduce Lifebench, which features densely connected, long-horizon event simulation. It pushes AI agents beyond simple recall, requiring the integration of declarative and non-declarative memory reasoning across diverse and temporally extended contexts. Building such a benchmark presents two key challenges: ensuring data quality and scalability. We maintain data quality by employing real-world priors, including anonymized social surveys, map APIs, and holiday-integrated calendars, thus enforcing fidelity, diversity and behavioral rationality within the dataset. Towards scalability, we draw inspiration from cognitive science and structure events according to their partonomic hierarchy; enabling efficient parallel generation while maintaining global coherence. Performance results show that top-tier, state-of-the-art memory systems reach just 55.2\% accuracy, highlighting the inherent difficulty of long-horizon retrieval and multi-source integration within our proposed benchmark. The dataset and data synthesis code are available at https://github.com/1754955896/LifeBench.

StegaFFD: Privacy-Preserving Face Forgery Detection via Fine-Grained Steganographic Domain Lifting

arXiv:2603.02886v1 Announce Type: cross Abstract: Most existing Face Forgery Detection (FFD) models assume access to raw face images. In practice, under a client-server framework, private facial data may be intercepted during transmission or leaked by untrusted servers. Previous privacy protection approaches, such as anonymization, encryption, or distortion, partly mitigate leakage but often introduce severe semantic distortion, making images appear obviously protected. This alerts attackers, provoking more aggressive strategies and turning the process into a cat-and-mouse game. Moreover, these methods heavily manipulate image contents, introducing degradation or artifacts that may confuse FFD models, which rely on extremely subtle forgery traces. Inspired by advances in image steganography, which enable high-fidelity hiding and recovery, we propose a Stega}nography-based Face Forgery Detection framework (StegaFFD) to protect privacy without raising suspicion. StegaFFD hides facial images within natural cover images and directly conducts forgery detection in the steganographic domain. However, the hidden forgery-specific features are extremely subtle and interfered with by cover semantics, posing significant challenges. To address this, we propose Low-Frequency-Aware Decomposition (LFAD) and Spatial-Frequency Differential Attention (SFDA), which suppress interference from low-frequency cover semantics and enhance hidden facial feature perception. Furthermore, we introduce Steganographic Domain Alignment (SDA) to align the representations of hidden faces with those of their raw counterparts, enhancing the model's ability to perceive subtle facial cues in the steganographic domain. Extensive experiments on seven FFD datasets demonstrate that StegaFFD achieves strong imperceptibility, avoids raising attackers' suspicion, and better preserves FFD accuracy compared to existing facial privacy protection methods.

Dynamic Manifold Hopfield Networks for Context-Dependent Associative Memory

arXiv:2506.01303v3 Announce Type: replace-cross Abstract: Neural population activity in cortical and hippocampal circuits can be flexibly reorganized by context, suggesting that cognition relies on dynamic manifolds rather than static representations. However, how such dynamic organization can be realized mechanistically within a unified dynamical system remains unclear. Continuous Hopfield networks provide a classical attractor framework in which neural dynamics follow gradient descent on a fixed energy landscape, constraining retrieval within a static attractor manifold geometry. Extending this approach, we introduce Dynamic Manifold Hopfield Networks (DMHN), continuous dynamical models in which contextual modulation dynamically reshapes attractor geometry, transforming a static attractor manifold into a context-dependent family of neural manifolds. In DMHN, network interactions are learned in a data-driven manner, to intrinsically deform the geometry of its attractor manifold across cues without explicit context-specific parameterization. As a result, in associative retrieval, DMHN achieve substantially higher capacity and robustness than classical and modern Hopfield networks: when storing $2N$ patterns in a network of $N$ neurons, DMHN attain reliable retrieval with an average accuracy of 64%, compared with 1% and 13% for classical and modern variants, respectively. Together, these results establish dynamic reorganization of attractor manifold geometry as a principled mechanism for context-dependent remapping in neural associative memory.

DMTrack: Spatio-Temporal Multimodal Tracking via Dual-Adapter

arXiv:2508.01592v2 Announce Type: replace-cross Abstract: In this paper, we explore adapter tuning and introduce a novel dual-adapter architecture for spatio-temporal multimodal tracking, dubbed DMTrack. The key of our DMTrack lies in two simple yet effective modules, including a spatio-temporal modality adapter (STMA) and a progressive modality complementary adapter (PMCA) module. The former, applied to each modality alone, aims to adjust spatio-temporal features extracted from a frozen backbone by self-prompting, which to some extent can bridge the gap between different modalities and thus allows better cross-modality fusion. The latter seeks to facilitate cross-modality prompting progressively with two specially designed pixel-wise shallow and deep adapters. The shallow adapter employs shared parameters between the two modalities, aiming to bridge the information flow between the two modality branches, thereby laying the foundation for following modality fusion, while the deep adapter modulates the preliminarily fused information flow with pixel-wise inner-modal attention and further generates modality-aware prompts through pixel-wise inter-modal attention. With such designs, DMTrack achieves promising spatio-temporal multimodal tracking performance with merely 0.93M trainable parameters. Extensive experiments on five benchmarks demonstrate that DMTrack achieves state-of-the-art results. Our code and models will be available at https://github.com/Nightwatch-Fox11/DMTrack.

QIME: Constructing Interpretable Medical Text Embeddings via Ontology-Grounded Questions

arXiv:2603.01690v2 Announce Type: replace-cross Abstract: While dense biomedical embeddings achieve strong performance, their black-box nature limits their utility in clinical decision-making. Recent question-based interpretable embeddings represent text as binary answers to natural-language questions, but these approaches often rely on heuristic or surface-level contrastive signals and overlook specialized domain knowledge. We propose QIME, an ontology-grounded framework for constructing interpretable medical text embeddings in which each dimension corresponds to a clinically meaningful yes/no question. By conditioning on cluster-specific medical concept signatures, QIME generates semantically atomic questions that capture fine-grained distinctions in biomedical text. Furthermore, QIME supports a training-free embedding construction strategy that eliminates per-question classifier training while further improving performance. Experiments across biomedical semantic similarity, clustering, and retrieval benchmarks show that QIME consistently outperforms prior interpretable embedding methods and substantially narrows the gap to strong black-box biomedical encoders, while providing concise and clinically informative explanations.

Reshaping MOFs text mining with a dynamic multi-agents framework of large language model

arXiv:2504.18880v4 Announce Type: replace Abstract: Accurately identifying the synthesis conditions of metal-organic frameworks (MOFs) is essential for guiding experimental design, yet remains challenging because relevant information in the literature is often scattered, inconsistent, and difficult to interpret. We present MOFh6, a large language model driven system that reads raw articles or crystal codes and converts them into standardized synthesis tables. It links related descriptions across paragraphs, unifies ligand abbreviations with full names, and outputs structured parameters ready for use. MOFh6 achieved 99% extraction accuracy, resolved 94.1% of abbreviation cases across five major publishers, and maintained a precision of 0.93 +/- 0.01. Processing a full text takes 9.6 s, locating synthesis descriptions 36 s, with 100 papers processed for USD 4.24. By replacing static database lookups with real-time extraction, MOFh6 reshapes MOF synthesis research, accelerating the conversion of literature knowledge into practical synthesis protocols and enabling scalable, data-driven materials discovery.

VideoMind: A Chain-of-LoRA Agent for Temporal-Grounded Video Reasoning

arXiv:2503.13444v3 Announce Type: replace-cross Abstract: Videos, with their unique temporal dimension, demand precise grounded understanding, where answers are directly linked to visual, interpretable evidence. Despite significant breakthroughs in text-based reasoning with large language models, multi-modal reasoning - especially for videos - remains limited. In this work, we fill this gap by introducing VideoMind, a novel video-language agent for temporal-grounded video reasoning. Our method involves two key innovations: (1) We identify four essential capabilities for grounded video reasoning and propose a role-based agentic workflow, comprising a planner to coordinate roles, a grounder for temporal event localization, a verifier to assess event candidates, and an answerer for question answering. (2) To efficiently integrate these roles during inference, we propose a novel Chain-of-LoRA mechanism, where a unified base model with multiple LoRA adapters is leveraged to enable seamless role switching, balancing efficiency and flexibility. Extensive experiments on 15 benchmarks across Grounded VideoQA, Video Temporal Grounding, and General VideoQA tasks demonstrate the effectiveness of the proposed scheme in advancing video agent, test-time scaling, and long-form video reasoning. Code, models, datasets, and demos are available at https://videomind.github.io/.

Silent Inconsistency in Data-Parallel Full Fine-Tuning: Diagnosing Worker-Level Optimization Misalignment

arXiv:2602.14462v1 Announce Type: cross Abstract: Data-parallel (DP) training with synchronous all-reduce is a dominant paradigm for full-parameter fine-tuning of large language models (LLMs). While parameter synchronization guarantees numerical equivalence of model weights after each iteration, it does not necessarily imply alignment of worker-level optimization dynamics before gradient aggregation. This paper identifies and studies this latent mismatch, termed \emph{silent inconsistency}, where cross-worker divergence in losses and gradients can remain invisible under conventional aggregated monitoring signals. We propose a lightweight, model-agnostic diagnostic framework that quantifies worker-level consistency using training signals readily available in standard pipelines. Specifically, we introduce three complementary metrics: loss dispersion, gradient-norm dispersion, and gradient-direction consistency measured by inter-worker cosine similarity. The proposed metrics incur negligible overhead and require no modification to model architecture, synchronization mechanisms, or optimization algorithms. We validate the framework by fully fine-tuning the 1B-parameter \texttt{openPangu-Embedded-1B-V1.1} model on the \texttt{tatsu-lab/alpaca} dataset using an 8-NPU DP setup, under controlled perturbations of cross-rank stochasticity. Experimental results show that progressively desynchronized data shuffling and random seeds lead to substantial increases in loss/gradient dispersion and reduced directional alignment, despite smooth globally averaged loss curves. These findings demonstrate that the proposed indicators provide actionable visibility into hidden instability modes in large-scale DP fine-tuning, enabling more reliable diagnosis and configuration assessment.
❌