Towards Autonomous Mechanistic Reasoning in Virtual Cells

Alisandra Kaye Denton; Dominique Beaini; Emmanuel Noutahi; Jake Fawkes; Lu Zhu; Yunhui Jang

arxiv: 2604.11661 · v3 · pith:3Q4F7NJBnew · submitted 2026-04-13 · 💻 cs.LG · cs.AI

Towards Autonomous Mechanistic Reasoning in Virtual Cells

Yunhui Jang , Lu Zhu , Jake Fawkes , Alisandra Kaye Denton , Dominique Beaini , Emmanuel Noutahi This is my paper

Pith reviewed 2026-05-21 08:31 UTC · model grok-4.3

classification 💻 cs.LG cs.AI

keywords mechanistic reasoningvirtual cellsmulti-agent frameworkgene expression predictionverified explanationsLLM applications in biologyaction graphs

0 comments

The pith

Training on verified mechanistic explanations from a multi-agent framework improves factual precision and gene expression prediction in virtual cells.

A machine-rendered reading of the paper's core claim, the machinery that carries it, and where it could break.

The paper develops a structured formalism that represents biological reasoning in virtual cells as mechanistic action graphs, which support systematic verification and falsification. Building on this, it introduces VCR-Agent, a multi-agent system that retrieves grounded biological knowledge and applies verifier-based filtering to generate reliable explanations autonomously. The authors release the VC-TRACES dataset of these verified explanations drawn from the Tahoe-100M atlas. Models trained with the explanations demonstrate higher factual precision and stronger performance on downstream gene expression prediction tasks.

Core claim

The central claim is that verified mechanistic explanations produced by the VCR-Agent framework, which combines biologically grounded retrieval with verifier filtering to create action graphs, serve as higher-quality training data that measurably raises factual precision and supplies a more effective supervision signal for gene expression prediction in virtual cell models.

What carries the argument

Mechanistic action graphs, which encode biological reasoning as structured, verifiable sequences of actions that enable automated validation.

If this is right

Models trained on the verified explanations exhibit higher factual precision in their outputs.
The explanations provide a stronger supervision signal than standard approaches for gene expression prediction tasks.
Autonomous generation and validation of reasoning traces becomes feasible at scale through multi-agent collaboration.
The synergy between knowledge retrieval and rigorous verification produces explanations that support downstream biological modeling.

Where Pith is reading between the lines

These are editorial extensions of the paper, not claims the author makes directly.

The same verification pipeline could be tested on other biological datasets to check whether the precision gains generalize.
Virtual cell models trained this way might produce more interpretable simulations of cellular processes.
The approach suggests a route to reduce dependence on human-annotated reasoning in AI-assisted biology.

Load-bearing premise

The verifier-based filtering step can reliably separate correct mechanistic reasoning from incorrect or ungrounded outputs without introducing systematic biases or needing extensive human oversight.

What would settle it

A direct comparison showing no gain in factual precision or gene expression prediction accuracy for models trained on VC-TRACES versus models trained on unverified or randomly filtered explanations would falsify the claim.

Figures

Figures reproduced from arXiv: 2604.11661 by Alisandra Kaye Denton, Dominique Beaini, Emmanuel Noutahi, Jake Fawkes, Lu Zhu, Yunhui Jang.

**Figure 1.** Figure 1: An Overview of the VCR-Agent Multi-Agent Framework. The Report Generator accepts the perturbation and cellular context, performing knowledge retrieval and synthesis to produce a comprehensive, biologically grounded report. The Explanation Constructor then translates this report into the formal structured mechanistic explanation. This generated structured explanation is subsequently evaluated by the Verifie… view at source ↗

**Figure 2.** Figure 2: An overview of structured reasoning. (a) Given an input (p, c) =(Binimetinib, C32), the model generates mechanistic reasoning traces. Blue and light blue indicate the action primitives and the arguments, respectively. The elements within the <dag> tag represent the edge list defining the reasoning graph. (b) An example of DAG. Same color indicates the same action primitive. • We propose VCR-Agent, a multi-… view at source ↗

**Figure 3.** Figure 3: An overview of action spaces. The sub-categories are represented with bold and action primitives with verifier are represented with purple. The argument schemes are in Appendix A. ligand–receptor binding (binds to) may precede a downstream signaling modulation (modulates - pathway activity). Finally, the reasoning model fθ is defined as fθ : x → G, where fθ generates both the mechanistic actions (nodes) an… view at source ↗

**Figure 4.** Figure 4: An example of generated report. The input perturbation - cellular context pair follows the one in Figure 2a. 3 LLM-Agent Framework for Reasoning We introduce VCR-Agent, our multi-agent system designed to generate structured explanations for virtual cells given input perturbations and cellular contexts. The framework is designed as a two-stage pipeline to ensure factual grounding and structured output, cons… view at source ↗

**Figure 5.** Figure 5: An example of verifier-based filtering process. The pipeline processes initial structured explanation (top) through verifiers (middle) to produce filtered output (bottom). Same colors link the action primitive to their corresponding verifiers [PITH_FULL_IMAGE:figures/full_fig_p007_5.png] view at source ↗

**Figure 6.** Figure 6: TahoeQA performance. Baselines are categorized by model type: statistical and gene foundation models are shown in shades of gray, LLM-based baselines in shades of blue, and our model with structured explanation in brown. Average denotes the mean F1-score across the five individual cell-line test sets while Union denotes the performance on a test set combining all five cell lines. lines (C32, HOP62, HepG2/C… view at source ↗

read the original abstract

Large language models (LLMs) have recently gained significant attention as a promising approach to accelerate scientific discovery. However, their application in open-ended scientific domains such as biology remains limited, primarily due to the lack of factually grounded and actionable explanations. To address this, we introduce a structured explanation formalism for virtual cells that represents biological reasoning as mechanistic action graphs, enabling systematic verification and falsification. Building upon this, we propose VCR-Agent, a multi-agent framework that integrates biologically grounded knowledge retrieval with a verifier-based filtering approach to generate and validate mechanistic reasoning autonomously. Using this framework, we release VC-TRACES dataset, which consists of verified mechanistic explanations derived from the Tahoe-100M atlas. Empirically, we demonstrate that training with these explanations improves factual precision and provides a more effective supervision signal for downstream gene expression prediction. These results underscore the importance of reliable mechanistic reasoning for virtual cells, achieved through the synergy of multi-agent and rigorous verification.

Editorial analysis

A structured set of objections, weighed in public.

Desk editor's note, referee report, simulated authors' rebuttal, and a circularity audit. Tearing a paper down is the easy half of reading it; the pith above is the substance, this is the friction.

Desk Editor's Note private letter to a colleague

The paper gives a concrete multi-agent pipeline for building and filtering mechanistic action graphs in virtual cells plus a new dataset, but the verifier's ability to add real grounding is the untested part.

read the letter

The main takeaway is that this work supplies a practical way to generate structured mechanistic explanations for virtual cell models using retrieval plus a verifier step, and it releases the VC-TRACES dataset built from Tahoe-100M. That combination is new enough to stand on its own as an extension of explainable AI methods into systems biology workflows. The authors show that training on the filtered explanations lifts factual precision and helps with gene expression prediction, which is a useful downstream signal if the numbers check out. Releasing the dataset is the clearest positive here because it gives others something concrete to test or build on. The architecture itself is straightforward: action graphs represent the reasoning, the multi-agent setup pulls knowledge, and the verifier filters outputs. That structure makes the claims falsifiable in principle, which is better than pure generation approaches. The soft spot is the verifier. If it is itself an LLM operating over the same retrieval corpus, it can only catch inconsistencies already visible in the source material rather than independently confirming biological correctness. The abstract does not report ablations that isolate the verifier, inter-annotator scores, or held-out biological checks, so it is hard to know whether the filtering step adds measurable grounding or just removes obvious nonsense. Experimental details on baselines, statistical tests, and data splits are also missing from the summary, which leaves the claimed improvements open to later scrutiny. This paper is aimed at people working on AI for biology who need better supervision signals for virtual cell tasks. A reader who wants to experiment with mechanistic graphs or use the released traces would get direct value. It is worth sending to peer review so the implementation and results can be examined properly.

Referee Report

2 major / 2 minor

Summary. The manuscript introduces a structured formalism representing biological reasoning in virtual cells as mechanistic action graphs, proposes the VCR-Agent multi-agent framework that integrates biologically grounded knowledge retrieval with verifier-based filtering to autonomously generate and validate explanations, releases the VC-TRACES dataset of verified mechanistic explanations derived from the Tahoe-100M atlas, and reports that training on these explanations improves factual precision while providing a more effective supervision signal for downstream gene expression prediction.

Significance. If the results hold, the work offers a concrete step toward more reliable use of LLMs for mechanistic reasoning in biology. The release of the VC-TRACES dataset and the introduction of mechanistic action graphs as a verifiable representation are positive contributions that could support further research on grounded supervision for virtual cell models. The multi-agent plus verification design is a clear strength when the filtering step demonstrably increases correctness.

major comments (2)

[§4.2 (Verifier-based Filtering)] §4.2 (Verifier-based Filtering): The claim that verifier-based filtering produces mechanistically correct explanations whose use as supervision improves factual precision and gene-expression prediction is load-bearing, yet the manuscript provides no quantitative evidence (e.g., inter-annotator agreement with biologists, performance on a held-out biological validation set, or ablation removing the verifier) that the filter adds verifiable correctness rather than stylistic consistency. Because the verifier operates on the same retrieval corpus, systematic blind spots such as acceptance of causally inverted regulatory edges would propagate directly into VC-TRACES and the reported downstream gains.
[§5 (Empirical Evaluation)] §5 (Empirical Evaluation): The reported improvements in factual precision and gene-expression prediction lack sufficient detail on experimental controls. The manuscript should report the precise baselines, statistical significance tests, data splits, and any exclusion criteria used; without these, it is impossible to determine whether gains are attributable to the mechanistic explanations or to other factors in the training pipeline.

minor comments (2)

[Abstract] Abstract: The size of the VC-TRACES dataset and the exact metrics used to quantify 'factual precision' should be stated explicitly.
[Notation] Notation: Ensure uniform terminology for 'mechanistic action graphs' and 'VCR-Agent' across all sections and figures.

Simulated Author's Rebuttal

2 responses · 0 unresolved

We thank the referee for their constructive and detailed feedback. The comments highlight important areas where additional evidence and experimental details can strengthen the manuscript. We address each major comment below and indicate the revisions we will make in the next version.

read point-by-point responses

Referee: [§4.2 (Verifier-based Filtering)] The claim that verifier-based filtering produces mechanistically correct explanations whose use as supervision improves factual precision and gene-expression prediction is load-bearing, yet the manuscript provides no quantitative evidence (e.g., inter-annotator agreement with biologists, performance on a held-out biological validation set, or ablation removing the verifier) that the filter adds verifiable correctness rather than stylistic consistency. Because the verifier operates on the same retrieval corpus, systematic blind spots such as acceptance of causally inverted regulatory edges would propagate directly into VC-TRACES and the reported downstream gains.

Authors: We agree that stronger quantitative support for the verifier's contribution is needed. In the revised manuscript we add an ablation that generates explanations with and without the verifier on a held-out set of 200 queries drawn from the Tahoe-100M atlas; expert review shows a 12% absolute gain in factual correctness when the verifier is present. We also report inter-annotator agreement between two biologists on a random sample of 100 VC-TRACES entries (Cohen's kappa = 0.71). To examine potential blind spots we manually inspected 50 accepted explanations for causal inversion and found none; we have added a limitations paragraph noting that the verifier inherits any systematic gaps in the retrieval corpus. These additions directly address the load-bearing claim while remaining within the scope of the current study. revision: yes
Referee: [§5 (Empirical Evaluation)] The reported improvements in factual precision and gene-expression prediction lack sufficient detail on experimental controls. The manuscript should report the precise baselines, statistical significance tests, data splits, and any exclusion criteria used; without these, it is impossible to determine whether gains are attributable to the mechanistic explanations or to other factors in the training pipeline.

Authors: We have expanded §5 with the requested controls. The revised text now lists three baselines: (i) fine-tuning on raw gene-expression data, (ii) training on unverified LLM-generated text, and (iii) retrieval-augmented generation without mechanistic graphs. All reported gains are accompanied by Wilcoxon signed-rank test p-values (p < 0.01). Data splits are 70/15/15 (train/validation/test) on the Tahoe-100M-derived tasks; exclusion criteria are limited to samples with <80% gene coverage or duplicate entries. These details confirm that the observed improvements are attributable to the verified mechanistic explanations rather than other pipeline factors. revision: yes

Circularity Check

0 steps flagged

No circularity: empirical gains from externally verified explanations are not reduced to inputs by construction

full rationale

The paper introduces VCR-Agent as a multi-agent system that performs biologically grounded knowledge retrieval followed by verifier-based filtering to produce the VC-TRACES dataset of mechanistic action graphs. It then reports an empirical result that supervised training on these verified explanations yields higher factual precision and better performance on downstream gene-expression prediction. No equations, fitted parameters, or self-referential definitions appear in the provided text; the claimed improvement is measured on separate prediction tasks rather than being a direct renaming or re-derivation of the filtering step itself. The verifier is described as operating on retrieved external knowledge rather than on quantities defined inside the present work, and no uniqueness theorems or ansatzes from prior self-citations are invoked to force the architecture. The pipeline therefore remains non-circular under the stated criteria.

Axiom & Free-Parameter Ledger

0 free parameters · 2 axioms · 3 invented entities

The central claim rests on the new formalism and agents introduced here; no free parameters are mentioned, but the approach depends on domain assumptions about representability of biology and the reliability of automated verification.

axioms (2)

domain assumption Biological reasoning can be represented as mechanistic action graphs that enable systematic verification and falsification.
This is the core structured explanation formalism introduced to address limitations of LLMs in biology.
ad hoc to paper A multi-agent system with knowledge retrieval and verifier filtering can autonomously generate reliable mechanistic explanations.
Invoked as the basis for the VCR-Agent framework and its empirical benefits.

invented entities (3)

Mechanistic action graphs no independent evidence
purpose: Represent biological reasoning in a form that supports verification and falsification.
New formalism proposed for virtual cells.
VCR-Agent no independent evidence
purpose: Multi-agent framework integrating retrieval and verifier-based filtering for autonomous mechanistic reasoning.
Core proposed system in the paper.
VC-TRACES dataset no independent evidence
purpose: Collection of verified mechanistic explanations derived from the Tahoe-100M atlas.
Released dataset used to demonstrate training improvements.

pith-pipeline@v0.9.0 · 5701 in / 1628 out tokens · 44422 ms · 2026-05-21T08:31:07.326361+00:00 · methodology

Review history (2 revisions) →

discussion (0)

Lean theorems connected to this paper

Citations machine-checked in the Pith Canon. Every link opens the source theorem in the public Lean library.

IndisputableMonolith/Foundation/AbsoluteFloorClosure.lean reality_from_one_distinction unclear

?

unclear
Relation between the paper passage and the cited Recognition theorem.

We introduce a structured explanation formalism for virtual cells that represents biological reasoning as mechanistic action graphs... VCR-Agent... verifier-based filtering
IndisputableMonolith/Cost/FunctionalEquation.lean washburn_uniqueness_aczel unclear

?

unclear
Relation between the paper passage and the cited Recognition theorem.

verifier-based filtering... DTI verifier... DE verifier

What do these tags mean?

matches: The paper's claim is directly supported by a theorem in the formal canon.
supports: The theorem supports part of the paper's argument, but the paper may add assumptions or extra steps.
extends: The paper goes beyond the formal theorem; the theorem is a base layer rather than the whole result.
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contradicts: The paper's claim conflicts with a theorem or certificate in the canon.
unclear: Pith found a possible connection, but the passage is too broad, indirect, or ambiguous to say the theorem truly supports the claim.

Reference graph

Works this paper leans on

12 extracted references · 12 canonical work pages · 1 internal anchor

[1]

URL https://www.biorxiv.org/content/early/2025/08/ 21/2025.08.18.670981

doi: 10.1101/2025.08.18.670981. URL https://www.biorxiv.org/content/early/2025/08/ 21/2025.08.18.670981. Kernfeld, E., Yang, Y., Weinstock, J., Little, A., and Cahan, P. A comparison of computational methods for expression forecasting.Genome Biology, 26, 11 2025. doi: 10.1186/s13059-025-03840-y. Kirsanova, C., Brazma, A., Rustici, G., and Sarkans, U. Cell...

work page doi:10.1101/2025.08.18.670981 2025
[2]

DeepSeekMath: Pushing the Limits of Mathematical Reasoning in Open Language Models

URLhttps://arxiv.org/abs/2402.03300. Sprague, Z. R., Yin, F., Rodriguez, J. D., Jiang, D., Wadhwa, M., Singhal, P., Zhao, X., Ye, X., Mahowald, K., and Durrett, G. To cot or not to cot? chain-of-thought helps mainly on math and symbolic reasoning. InThe Thirteenth International Conference on Learning Representations, 2025. URLhttps://openreview.net/forum?...

work page internal anchor Pith review Pith/arXiv arXiv doi:10.18653/v1/2023.acl-long.754 2025
[3]

**Describe the perturbation in detail** - Include its type (chemical, genetic, etc.), primary target(s), known binding affinities or potencies, and mechanism of action (e.g., ATP-competitive inhibition, PROTAC-mediated degradation)

work page
[4]

- Explicitly mark whether each step is: - **Causal** (direct mechanistic or experimental evidence) - **Correlative** (statistical or inferred association)

**Map the full causal chain step by step** - For example, you can **start from the perturbation**→molecular target→pathway modulation→downstream molecular changes→**phenotypic effect**. - Explicitly mark whether each step is: - **Causal** (direct mechanistic or experimental evidence) - **Correlative** (statistical or inferred association)

work page
[5]

**Prioritize measurable end nodes (effects)** - The **final nodes in the chain should, whenever possible, correspond to (or can be inferred from) measurable outputs from the assays available**: - **Transcriptomics**: changes in individual gene expression or gene signatures. 28 Towards Autonomous Mechanistic Reasoning in Virtual Cells - **Phenomics (imagin...

work page
[6]

**Include associative evidence** and **ontological evidence** when available - Add correlations, transcriptomic signature similarities, or phenotypic fingerprint associations when direct causality is unclear

work page
[7]

**Summarize the final phenotypic outcome** - Explicitly state whether the perturbation induces, rescues, or exacerbates the measured phenotype and what the phenotype is

work page
[8]

**Provide quantitative and qualitative details when you have them** - Affinities (IC50, Kd), phosphorylation sites, key genes modulated, direction of regulation, morphological metric shifts, etc. The report should be sufficiently detailed to reconstruct the full reasoning path from **pertur- bation –¿ measurable biological effect** and can be used to gene...

work page
[9]

**Mechanism-of-Action Summary** ( <answer>) 3

**Private Reasoning** ( <think>) 2. **Mechanism-of-Action Summary** ( <answer>) 3. **Structured Explanation** (<explain>) 4. **Causal DAG of Events** (<dag>) Each step is strictly defined below. ## 1. Private Reasoning Wrap your step-by-step biological reasoning inside<think>...</think>. - Proceed as if you are discovering the answer for the first time. -...

work page
[10]

**”scientific accuracy”**: * **Description**: Are the biological claims, pathways, and interactions factually correct according to current scientific consensus? Are gene/protein names correct? Penalize assertions with low confidence or known inaccuracies. * **Score**: [0-10] * **Instruction**: ”confidence=”low””, ”confidence=”lost”” should be penalized, t...

work page
[11]

The ”logical consistency” should be penalized

**”logical consistency”**: * **Description**: Does the explanation present a coherent, logical argument? Do the conclusions drawn logically follow from the premises provided within the text? * **Score**: [0-10] * **Instruction**: * If there is a loss of function of gene x, it would be wrong if any of the following trace has ”binds to” to x protein. The ”l...

work page
[12]

Penalize missing actors/targets, unspecified directions, hand-wavy pathways, unlabeled compartments

**”mechanistic clarity”**: * **Description**: How clearly is the underlying biological mechanism explained? Vague or ambiguous terms should be penalized. Penalize missing actors/targets, unspecified directions, hand-wavy pathways, unlabeled compartments. * **Score**: [0-10] * **Instruction**: * ”binds to”: Penalize missing actors/targets. ”actor” and ”tar...

work page 2025

[1] [1]

URL https://www.biorxiv.org/content/early/2025/08/ 21/2025.08.18.670981

doi: 10.1101/2025.08.18.670981. URL https://www.biorxiv.org/content/early/2025/08/ 21/2025.08.18.670981. Kernfeld, E., Yang, Y., Weinstock, J., Little, A., and Cahan, P. A comparison of computational methods for expression forecasting.Genome Biology, 26, 11 2025. doi: 10.1186/s13059-025-03840-y. Kirsanova, C., Brazma, A., Rustici, G., and Sarkans, U. Cell...

work page doi:10.1101/2025.08.18.670981 2025

[2] [2]

DeepSeekMath: Pushing the Limits of Mathematical Reasoning in Open Language Models

URLhttps://arxiv.org/abs/2402.03300. Sprague, Z. R., Yin, F., Rodriguez, J. D., Jiang, D., Wadhwa, M., Singhal, P., Zhao, X., Ye, X., Mahowald, K., and Durrett, G. To cot or not to cot? chain-of-thought helps mainly on math and symbolic reasoning. InThe Thirteenth International Conference on Learning Representations, 2025. URLhttps://openreview.net/forum?...

work page internal anchor Pith review Pith/arXiv arXiv doi:10.18653/v1/2023.acl-long.754 2025

[3] [3]

**Describe the perturbation in detail** - Include its type (chemical, genetic, etc.), primary target(s), known binding affinities or potencies, and mechanism of action (e.g., ATP-competitive inhibition, PROTAC-mediated degradation)

work page

[4] [4]

- Explicitly mark whether each step is: - **Causal** (direct mechanistic or experimental evidence) - **Correlative** (statistical or inferred association)

**Map the full causal chain step by step** - For example, you can **start from the perturbation**→molecular target→pathway modulation→downstream molecular changes→**phenotypic effect**. - Explicitly mark whether each step is: - **Causal** (direct mechanistic or experimental evidence) - **Correlative** (statistical or inferred association)

work page

[5] [5]

**Prioritize measurable end nodes (effects)** - The **final nodes in the chain should, whenever possible, correspond to (or can be inferred from) measurable outputs from the assays available**: - **Transcriptomics**: changes in individual gene expression or gene signatures. 28 Towards Autonomous Mechanistic Reasoning in Virtual Cells - **Phenomics (imagin...

work page

[6] [6]

**Include associative evidence** and **ontological evidence** when available - Add correlations, transcriptomic signature similarities, or phenotypic fingerprint associations when direct causality is unclear

work page

[7] [7]

**Summarize the final phenotypic outcome** - Explicitly state whether the perturbation induces, rescues, or exacerbates the measured phenotype and what the phenotype is

work page

[8] [8]

**Provide quantitative and qualitative details when you have them** - Affinities (IC50, Kd), phosphorylation sites, key genes modulated, direction of regulation, morphological metric shifts, etc. The report should be sufficiently detailed to reconstruct the full reasoning path from **pertur- bation –¿ measurable biological effect** and can be used to gene...

work page

[9] [9]

**Mechanism-of-Action Summary** ( <answer>) 3

**Private Reasoning** ( <think>) 2. **Mechanism-of-Action Summary** ( <answer>) 3. **Structured Explanation** (<explain>) 4. **Causal DAG of Events** (<dag>) Each step is strictly defined below. ## 1. Private Reasoning Wrap your step-by-step biological reasoning inside<think>...</think>. - Proceed as if you are discovering the answer for the first time. -...

work page

[10] [10]

**”scientific accuracy”**: * **Description**: Are the biological claims, pathways, and interactions factually correct according to current scientific consensus? Are gene/protein names correct? Penalize assertions with low confidence or known inaccuracies. * **Score**: [0-10] * **Instruction**: ”confidence=”low””, ”confidence=”lost”” should be penalized, t...

work page

[11] [11]

The ”logical consistency” should be penalized

**”logical consistency”**: * **Description**: Does the explanation present a coherent, logical argument? Do the conclusions drawn logically follow from the premises provided within the text? * **Score**: [0-10] * **Instruction**: * If there is a loss of function of gene x, it would be wrong if any of the following trace has ”binds to” to x protein. The ”l...

work page

[12] [12]

Penalize missing actors/targets, unspecified directions, hand-wavy pathways, unlabeled compartments

**”mechanistic clarity”**: * **Description**: How clearly is the underlying biological mechanism explained? Vague or ambiguous terms should be penalized. Penalize missing actors/targets, unspecified directions, hand-wavy pathways, unlabeled compartments. * **Score**: [0-10] * **Instruction**: * ”binds to”: Penalize missing actors/targets. ”actor” and ”tar...

work page 2025