Searcharxiv⌕ Search

arXiv subjects

Zhangyang Gao

Publications and source records attributed to Zhangyang Gao.

At least 19 recordsLinked to original sources
arXiv2026

E$^2$-OPSD: Taming Entropy Overshoot in On-Policy Self-Distillation

On-policy self-distillation (OPSD) provides dense token-level supervision without a second model: one network acts as teacher with the reference solution and as student with only the problem. We identify a specific failure mode of this recipe. During training, student token entropy rises past the teacher's and remains elevated, a pattern we call entropy overshoot. We trace it to both sides of distillation. The reference-conditioned teacher is confident along its answer-directed reasoning path, but this confidence transfers poorly to student-generated prefixes, making its supervision overly tied to answer-specific cues rather than reusable reasoning patterns; meanwhile, the forward KL used by OPSD continually diffuses the student's predictive distribution without pulling it back. We introduce E$^2$-OPSD to address both causes. Exemplar-guided teaching replaces the current answer with a retrieved solved neighboring problem, providing transferable reasoning guidance without revealing the destination and better matching student-reachable states. Entropy-aware distillation uses the student-teacher entropy gap to determine the direction and strength of each token's correction. E$^2$-OPSD improves math reasoning by up to 4.3 points in mean@16 over OPSD, while out-of-domain evaluations show gains over the corresponding base models of up to 4.9 points in mean@16 and 5.5 points in pass@8. Despite these gains, E$^2$-OPSD remains simple, requiring no additional forward passes or networks. Code repo: https://github.com/orionfei/E2-OPSD.

cs.LG↗
arXiv2026

CellChain: Benchmarking Cross-Scale Evidence Use for Perturbation Reasoning

Recent advances in foundation models and large-scale cellular perturbation datasets have driven growing interest in using LLMs to predict and reason about cellular responses. Biological reasoning in this setting involves relating molecular mechanisms, cellular responses, and functional outcomes across scales. Evaluating foundation models therefore requires assessing not only whether their predictions are correct, but also how those predictions depend on the biological evidence provided. We introduce CellChain, an experimentally grounded benchmark comprising 590 biological cases and 2,360 matched evidence-condition instances across gene-dependency prediction, cytokine-axis identification, and drug-sensitivity ranking. CellChain links perturbation experiments and external biological resources through a provenance-aware evidence graph spanning molecular, pathway, transcriptional, and phenotypic information. Task-specific conditions vary evidence coverage, composition, or assignment while preserving questions, candidate answers, reference targets, and scoring rules. Across 18 foundation models, the highest accuracies under prespecified target-evidence conditions are 57.5%, 75.5%, and 70.8%, respectively, and broader evidence coverage does not consistently improve accuracy. On the drug-sensitivity benchmark cohort, matched reference histories outperform swapped histories by an average of 13.0 percentage points in cluster-weighted accuracy. Decision-transition analysis separates corrections, newly introduced errors, and wrong-answer switches, revealing substantial answer changes hidden by small net accuracy differences. CellChain provides controlled comparisons for attributing changes in model predictions to prespecified expansions of biological context, including changes in evidence coverage, composition, and biological assignment.

cs.DB↗
arXiv2026

MindFlow: Mind Supernet Powered Thinking Flows for Research Idea Innovation

Research idea innovation is a fundamental engine of scientific progress, yet it remains difficult to generate and evaluate in a scalable and controllable way. This challenge lies in its inherently open-ended and multi-objective nature, where ideas should balance novelty, plausibility and feasibility. While recent LLM-based approaches have made progress through carefully designed prompts or agent pipelines, they are constrained by predefined, static ideation workflows. To address this limitation, we propose MindFlow, a framework that explicitly formulates ideation as a graph-structured Flow in Mind, which is composed of modular thinking operators and modeled by a probabilistic mind supernet. Given a research topic, a controller dynamically samples thinking flows to generate candidate ideas. This open-ended problem is optimized using a tournament-based relative ranking, enabling the controller to progressively favor higher-quality thinking flows. We further introduce an evaluation protocol that jointly assesses problem finding and problem solving, going beyond title- or abstractonly judgments. Across diverse topics, MindFlow shows its superiority as an explicit, controllable and optimizable research idea innovator.

cs.AI↗
arXiv2026

SCALE:Scalable Conditional Atlas-Level Endpoint transport for virtual cell perturbation prediction

Virtual-cell models aim to predict how cell populations respond to perturbations, but control and treated cells are measured as unpaired populations, complicating the learning of perturbation-specific effects. We present SCALE, a conditional transport model that represents cells as unordered sets and predicts treated populations without cell-level matching. A shared set-aware encoder and conditional DiT backbone learn latent transport, making endpoint supervision directly delta-aligned without an auxiliary delta objective. Across genetic, chemical, developmental and immune perturbations, SCALE recovered gene-expression changes, response directions and population structure. In CRISPR data with dominant cell-line effects, SCALE outperformed competing methods across seven metrics and maintained separation among gene-target representations rather than collapsing them into a shared region. SCALE further prioritized cytokines predicted to produce distinct immune activation and inflammatory responses. Experiments using matched PBMC samples from three donors confirmed these predicted differences. Together, SCALE enables perturbation-specific prediction from unpaired populations and supports experimental prioritization.

cs.LG↗
arXiv2026

When LLM Meets Tree Search: A Systematic View of Inference as Search in Large Language Models

As pretraining scaling laws approach saturation, Test-Time Scaling (TTS) has emerged as an important direction for improving reasoning by allocating inference-time compute to a fixed model prior. Viewed at a high level, TTS reframes inference as search over a space of partial reasoning states. While Chain-of-Thought (CoT) exposes intermediate steps, common instantiations rely on single-trajectory decoding, limiting recovery from early errors and exploration. This survey systematizes recent progress in tree-search-based reasoning, viewing inference as instance-specific optimization rather than decoding. We trace the evolution from uninformed search to Monte Carlo Tree Search (MCTS), highlighting how sampling-based control supports principled exploration-exploitation trade-offs. To unify a fragmented literature, we introduce a Unified Design Space spanning search topology, evaluation signals, and control dynamics, and advocate a standardized compute-reporting abstraction to make compute-accuracy trade-offs explicit and comparable.

cs.CL↗
arXiv2026

SciForge: An AI-Native, Multimodal Workbench for Scientific Discovery

Scientific work increasingly spans heterogeneous artifacts -- papers, code, datasets, scientific file formats, model outputs, figures, manuscripts, and team decisions -- yet general-purpose AI assistants rarely preserve these objects as a coherent, auditable research state. We present SciForge, a multimodal research-native AI workbench that reserves the graphical interface for human judgment while search, parsing, model routing, workflow execution, plotting, writing, and presentation generation run as modular agent-accessible services. SciForge is built around five pillars: (i) \emph{goal-scoped scientific decision governance} for \textbf{goal-oriented} research, with review gates and shared review surfaces; (ii) \emph{translate-then-reason} for \textbf{multimodal} input, routing scientific objects through domain translators before the agent reasons; (iii) \emph{evidence governance} for \textbf{auditable} traceability, linking claims to provenance chains and audit findings; (iv) \emph{collaborative team science} for \textbf{collaborative} research, enabling multi-role decision governance, with shared team workspaces planned for future releases; and (v) \emph{real-world application scenarios} for \textbf{practical} impact, demonstrated through eight end-to-end user cases, with flagship demonstrations including multi-day agentic research sprints for gene discovery, AI-guided de novo protein design, molecular optimization, and genome-to-BGC discovery. The system combines a thin interaction layer, contextual research capability patterns, an Agent Runtime and Workflow Engine, an Evidence-DAG audit sidecar and a Scientific Model Router. SciForge currently runs as a desktop application, with mobile supervision support; future releases will deepen team collaboration. The system is open-source and available at https://github.com/AGI4Sci/SciForge

cs.AI↗
arXiv2026

Accurate, Interdisciplinary and Transparent Structure-property Understanding with Deep Native Structural Reasoning

Structure-property relationships are foundational to biology, chemistry and materials science, where function, reactivity and physical response emerge from spatial, chemical and periodic organization. Mechanistically explaining these relationships requires interpreting structural evidence through scientific principles and physical constraints, from stereochemistry and bonding to symmetry, energetics and periodic order. However, applying artificial intelligence to this process presents a joint challenge of representation and reasoning: models must preserve domain-native structural information while showing how specific evidence supports predictions under these constraints. Here we introduce SciReasoner, a multimodal scientific foundation model for native structural reasoning across proteins, small molecules and inorganic crystals. SciReasoner discretizes coordinates, topologies and periodic connectivities into a unified structure-aware vocabulary, treating structural tokens as addressable evidence units during reasoning. In homology-controlled Gene Ontology prediction, SciReasoner improves Cellular Component annotation for low-homology and orphan-like proteins, increasing $F_{\max}$ from 0.42 to 0.55. In chemistry, it raises single-step retrosynthesis accuracy from 0.63 to 0.72 while generating fragment-level disconnection and precursor-verification traces. In materials science, its representations separate elemental and compound phases and resolve high- and low-band-gap regimes. Across 86 benchmarks, SciReasoner achieves state-of-the-art performance on 67 tasks. Double-blind expert evaluation rates its reasoning traces as preferred or at least comparable to those of a frontier large language model in 98% of cases. By making structure an inspectable substrate for reasoning under scientific constraints, SciReasoner connects accurate prediction with interpretable scientific inference.

cs.CL↗
arXiv2026

AblateCell: A Reproduce-then-Ablate Agent for Virtual Cell Repositories

Systematic ablations are essential to attribute performance gains in AI Virtual Cells, yet they are rarely performed because biological repositories are under-standardized and tightly coupled to domain-specific data and formats. While recent coding agents can translate ideas into implementations, they typically stop at producing code and lack a verifier that can reproduce strong baselines and rigorously test which components truly matter. We introduce AblateCell, a reproduce-then-ablate agent for virtual cell repositories that closes this verification gap. AblateCell first reproduces reported baselines end-to-end by auto-configuring environments, resolving dependency and data issues, and rerunning official evaluations while emitting verifiable artifacts. It then conducts closed-loop ablation by generating a graph of isolated repository mutations and adaptively selecting experiments under a reward that trades off performance impact and execution cost. Evaluated on three single-cell perturbation prediction repositories (CPA, GEARS, BioLORD), AblateCell achieves 88.9% (+29.9% to human expert) end-to-end workflow success and 93.3% (+53.3% to heuristic) accuracy in recovering ground-truth critical components. These results enable scalable, repository-grounded verification and attribution directly on biological codebases.

cs.AI↗
arXiv2026

Benchmarking virtual cell models for in-the-wild perturbation response

Virtual cell (VC) models aim to predict cellular responses to any perturbations in silico and have emerged as a promising approach for drug discovery and precision medicine. Yet, a clear gap still remains: while models routinely reported impressive results on standard benchmarks, it is unclear whether their predictions are truly meaningful in practice. This is mainly due to limitations in current evaluation setups, which are often overly simplified or inconsistent, and do not reflect the complexity and variability of real biological systems. Here, we introduce a standardized and modular benchmarking framework for virtual cell prediction. Our framework evaluates diverse models under in-the-wild challenging scenarios, including unseen cell contexts, unseen perturbations, and cross-dataset generalization, which better reflect practical applications. Our analysis shows that model performance is highly context-dependent and shaped by task design and evaluation criteria. In commonly used setups, performance is often overestimated, and naive dataset aggregation can even reduce performance. When evaluated under more strict conditions, model performance drops markedly, indicating limited robustness to shifts across cellular contexts. In unseen perturbation settings, models including simple linear approaches capture global transcriptional trends but fail to recover fine-grained perturbation-specific effects. In addition, different evaluation metrics focus on different biological properties, leading to substantially different model rankings. Together, our framework provides a more reliable and biologically grounded evaluation, offering clearer guidance for applying virtual cell models in real scenarios.

q-bio.CB↗
arXiv2026

HarmonyCell: Automating Single-Cell Perturbation Modeling under Semantic and Distribution Shifts

Single-cell perturbation studies face dual heterogeneity bottlenecks: (i) semantic heterogeneity--identical biological concepts encoded under incompatible metadata schemas across datasets; and (ii) statistical heterogeneity--distribution shifts from biological variation demanding dataset-specific inductive biases. We propose HarmonyCell, an end-to-end agent framework resolving each challenge through a dedicated mechanism: an LLM-driven Semantic Unifier autonomously maps disparate metadata into a canonical interface without manual intervention; and an adaptive Monte Carlo Tree Search engine operates over a hierarchical action space to synthesize architectures with optimal statistical inductive biases for distribution shifts. Evaluated across diverse perturbation tasks under both semantic and distribution shifts, HarmonyCell achieves a 95% valid execution rate on heterogeneous input datasets (versus 0% for general agents) while matching or even exceeding expert-designed baselines in rigorous out-of-distribution evaluations. This dual-track orchestration enables scalable automatic virtual cell modeling without dataset-specific engineering.

cs.AI↗
arXiv2026

SciDataCopilot: An Agentic Data Preparation Framework for AGI-driven Scientific Discovery

The current landscape of AI for Science (AI4S) is predominantly anchored in large-scale textual corpora, where generative AI systems excel at hypothesis generation, literature search, and multi-modal reasoning. However, a critical bottleneck for accelerating closed-loop scientific discovery remains the utilization of raw experimental data. Characterized by extreme heterogeneity, high specificity, and deep domain expertise requirements, raw data possess neither direct semantic alignment with linguistic representations nor structural homogeneity suitable for a unified embedding space. The disconnect prevents the emerging class of Artificial General Intelligence for Science (AGI4S) from effectively interfacing with the physical reality of experimentation. In this work, we extend the text-centric AI-Ready concept to Scientific AI-Ready data paradigm, explicitly formalizing how scientific data is specified, structured, and composed within a computational workflow. To operationalize this idea, we propose SciDataCopilot, an autonomous agentic framework designed to handle data ingestion, scientific intent parsing, and multi-modal integration in a end-to-end manner. By positioning data readiness as a core operational primitive, the framework provides a principled foundation for reusable, transferable systems, enabling the transition toward experiment-driven scientific general intelligence. Extensive evaluations across three heterogeneous scientific domains show that SciDataCopilot improves efficiency, scalability, and consistency over manual pipelines, with up to 30$\times$ speedup in data preparation.

cs.DB↗
arXiv2025

Lost in Tokenization: Context as the Key to Unlocking Biomolecular Understanding in Scientific LLMs

Scientific Large Language Models (Sci-LLMs) have emerged as a promising frontier for accelerating biological discovery. However, these models face a fundamental challenge when processing raw biomolecular sequences: the tokenization dilemma. Whether treating sequences as a specialized language, risking the loss of functional motif information, or as a separate modality, introducing formidable alignment challenges, current strategies fundamentally limit their reasoning capacity. We challenge this sequence-centric paradigm by positing that a more effective strategy is to provide Sci-LLMs with high-level structured context derived from established bioinformatics tools, thereby bypassing the need to interpret low-level noisy sequence data directly. Through a systematic comparison of leading Sci-LLMs on biological reasoning tasks, we tested three input modes: sequence-only, context-only, and a combination of both. Our findings are striking: the context-only approach consistently and substantially outperforms all other modes. Even more revealing, the inclusion of the raw sequence alongside its high-level context consistently degrades performance, indicating that raw sequences act as informational noise, even for models with specialized tokenization schemes. These results suggest that the primary strength of existing Sci-LLMs lies not in their nascent ability to interpret biomolecular syntax from scratch, but in their profound capacity for reasoning over structured, human-readable knowledge. Therefore, we argue for reframing Sci-LLMs not as sequence decoders, but as powerful reasoning engines over expert knowledge. This work lays the foundation for a new class of hybrid scientific AI agents, repositioning the developmental focus from direct sequence interpretation towards high-level knowledge synthesis. The code is available at https://github.com/opendatalab-raiser/CoKE.

cs.AI↗
arXiv2025

From AI for Science to Agentic Science: A Survey on Autonomous Scientific Discovery

Artificial intelligence (AI) is reshaping scientific discovery, evolving from specialized computational tools into autonomous research partners. We position Agentic Science as a pivotal stage within the broader AI for Science paradigm, where AI systems progress from partial assistance to full scientific agency. Enabled by large language models (LLMs), multimodal systems, and integrated research platforms, agentic AI shows capabilities in hypothesis generation, experimental design, execution, analysis, and iterative refinement -- behaviors once regarded as uniquely human. This survey provides a domain-oriented review of autonomous scientific discovery across life sciences, chemistry, materials science, and physics. We unify three previously fragmented perspectives -- process-oriented, autonomy-oriented, and mechanism-oriented -- through a comprehensive framework that connects foundational capabilities, core processes, and domain-specific realizations. Building on this framework, we (i) trace the evolution of AI for Science, (ii) identify five core capabilities underpinning scientific agency, (iii) model discovery as a dynamic four-stage workflow, (iv) review applications across the above domains, and (v) synthesize key challenges and future opportunities. This work establishes a domain-oriented synthesis of autonomous scientific discovery and positions Agentic Science as a structured paradigm for advancing AI-driven research.

cs.LG↗
arXiv2025

Unifying Tree Search Algorithm and Reward Design for LLM Reasoning: A Survey

Deliberative tree search is a cornerstone of modern Large Language Model (LLM) research, driving the pivot from brute-force scaling toward algorithmic efficiency. This single paradigm unifies two critical frontiers: \textbf{Test-Time Scaling (TTS)}, which deploys on-demand computation to solve hard problems, and \textbf{Self-Improvement}, which uses search-generated data to durably enhance model parameters. However, this burgeoning field is fragmented and lacks a common formalism, particularly concerning the ambiguous role of the reward signal -- is it a transient heuristic or a durable learning target? This paper resolves this ambiguity by introducing a unified framework that deconstructs search algorithms into three core components: the \emph{Search Mechanism}, \emph{Reward Formulation}, and \emph{Transition Function}. We establish a formal distinction between transient \textbf{Search Guidance} for TTS and durable \textbf{Parametric Reward Modeling} for Self-Improvement. Building on this formalism, we introduce a component-centric taxonomy, synthesize the state-of-the-art, and chart a research roadmap toward more systematic progress in creating autonomous, self-improving agents.

cs.CL↗
arXiv2025

SketchAgent: Generating Structured Diagrams from Hand-Drawn Sketches

Hand-drawn sketches are a natural and efficient medium for capturing and conveying ideas. Despite significant advancements in controllable natural image generation, translating freehand sketches into structured, machine-readable diagrams remains a labor-intensive and predominantly manual task. The primary challenge stems from the inherent ambiguity of sketches, which lack the structural constraints and semantic precision required for automated diagram generation. To address this challenge, we introduce SketchAgent, a multi-agent system designed to automate the transformation of hand-drawn sketches into structured diagrams. SketchAgent integrates sketch recognition, symbolic reasoning, and iterative validation to produce semantically coherent and structurally accurate diagrams, significantly reducing the need for manual effort. To evaluate the effectiveness of our approach, we propose the Sketch2Diagram Benchmark, a comprehensive dataset and evaluation framework encompassing eight diverse diagram categories, such as flowcharts, directed graphs, and model architectures. The dataset comprises over 6,000 high-quality examples with token-level annotations, standardized preprocessing, and rigorous quality control. By streamlining the diagram generation process, SketchAgent holds great promise for applications in design, education, and engineering, while offering a significant step toward bridging the gap between intuitive sketching and machine-readable diagram generation. The benchmark is released at https://huggingface.co/datasets/DiagramAgent/Sketch2Diagram-Benchmark.

cs.AI↗
arXiv2025

Protein-SE(3): Benchmarking SE(3)-based Generative Models for Protein Structure Design

SE(3)-based generative models have shown great promise in protein geometry modeling and effective structure design. However, the field currently lacks a modularized benchmark to enable comprehensive investigation and fair comparison of different methods. In this paper, we propose Protein-SE(3), a new benchmark based on a unified training framework, which comprises protein scaffolding tasks, integrated generative models, high-level mathematical abstraction, and diverse evaluation metrics. Recent advanced generative models designed for protein scaffolding, from multiple perspectives like DDPM (Genie1 and Genie2), Score Matching (FrameDiff and RfDiffusion) and Flow Matching (FoldFlow and FrameFlow) are integrated into our framework. All integrated methods are fairly investigated with the same training dataset and evaluation metrics. Furthermore, we provide a high-level abstraction of the mathematical foundations behind the generative models, enabling fast prototyping of future algorithms without reliance on explicit protein structures. Accordingly, we release the first comprehensive benchmark built upon unified training framework for SE(3)-based protein structure design, which is publicly accessible at https://github.com/BruthYU/protein-se3.

cs.LG↗
arXiv2025

AlphaFold Database Debiasing for Robust Inverse Folding

The AlphaFold Protein Structure Database (AFDB) offers unparalleled structural coverage at near-experimental accuracy, positioning it as a valuable resource for data-driven protein design. However, its direct use in training deep models that are sensitive to fine-grained atomic geometry, such as inverse folding, exposes a critical limitation. Comparative analysis of structural feature distributions reveals that AFDB structures exhibit distinct statistical regularities, reflecting a systematic geometric bias that deviates from the conformational diversity found in experimentally determined structures from the Protein Data Bank (PDB). While AFDB structures are cleaner and more idealized, PDB structures capture the intrinsic variability and physical realism essential for generalization in downstream tasks. To address this discrepancy, we introduce a Debiasing Structure AutoEncoder (DeSAE) that learns to reconstruct native-like conformations from intentionally corrupted backbone geometries. By training the model to recover plausible structural states, DeSAE implicitly captures a more robust and natural structural manifold. At inference, applying DeSAE to AFDB structures produces debiased structures that significantly improve inverse folding performance across multiple benchmarks. This work highlights the critical impact of subtle systematic biases in predicted structures and presents a principled framework for debiasing, significantly boosting the performance of structure-based learning tasks like inverse folding.

cs.LG↗
arXiv2025

ProtInvTree: Deliberate Protein Inverse Folding with Reward-guided Tree Search

Designing protein sequences that fold into a target 3D structure, known as protein inverse folding, is a fundamental challenge in protein engineering. While recent deep learning methods have achieved impressive performance by recovering native sequences, they often overlook the one-to-many nature of the problem: multiple diverse sequences can fold into the same structure. This motivates the need for a generative model capable of designing diverse sequences while preserving structural consistency. To address this trade-off, we introduce ProtInvTree, the first reward-guided tree-search framework for protein inverse folding. ProtInvTree reformulates sequence generation as a deliberate, step-wise decision-making process, enabling the exploration of multiple design paths and exploitation of promising candidates through self-evaluation, lookahead, and backtracking. We propose a two-stage focus-and-grounding action mechanism that decouples position selection and residue generation. To efficiently evaluate intermediate states, we introduce a jumpy denoising strategy that avoids full rollouts. Built upon pretrained protein language models, ProtInvTree supports flexible test-time scaling by expanding the search depth and breadth without retraining. Empirically, ProtInvTree outperforms state-of-the-art baselines across multiple benchmarks, generating structurally consistent yet diverse sequences, including those far from the native ground truth.

q-bio.BM↗