arXiv subjects

Xiangxiang Zeng

Publications and source records attributed to Xiangxiang Zeng.

At least 19 recordsLinked to original sources

arXiv2026

AgentFold: Closed-Loop Agentic Search for Protein Folding Model Design

Scientific LLM agents have shown promise in literature reasoning, tool use, and experiment planning, but it remains unclear whether they can autonomously improve large, tightly coupled scientific machine-learning systems through executable code changes and computationally expensive validation. We study this question in protein folding, where progress requires coordinated architectural modifications, multi-objective evaluation, and domain-aware interpretation. We present AgentFold, a multi-agent framework that formulates folding-model development as a closed-loop search over executable code variants. Starting from ESMFold, AgentFold proposes hypotheses, implements and debugs code-level modifications, evaluates model variants, analyzes experimental outcomes, and stores both successful and failed interventions in structured memory. An MCTS-style policy allocates computational resources across high-scoring search branches. On an engineering-scale protein-folding codebase comprising more than 2,000 lines of code, AgentFold explores approximately 80 model variants using approximately 5,000 GPU-hours and 170 million LLM tokens. Under a matched computational budget, AgentFold improves the best lDDT by 7.5% over independent Codex proposals and outperforms a random-search control. Beyond model improvement, the resulting intervention traces reveal recurring empirical design patterns: stable gains tend to arise from early, soft, learnable priors and gated refinement, whereas direct geometric perturbations and geometry-conditioned feedback often destabilize training. The code and experimental resources are publicly available at https://github.com/lmqfly/AgentFold.

cs.AI↗

arXiv2026

Simulation-to-real transfer learning for infrared spectroscopic chemical sensing and analysis from molecules to complex samples

Infrared (IR) spectroscopy is widely used for chemical sensing, but extracting reliable chemical information from spectra remains challenging. Conventional interpretation is labor-intensive, relies on prior knowledge and reference spectra, and is difficult to scale, whereas most machine-learning methods are tailored to individual tasks or datasets, require large labeled training sets, and transfer poorly across analytical objectives and experimental datasets. Here we introduce UltraIR, a foundation model for IR spectroscopy with more than 100 million parameters that enables simulation-to-real transfer learning for chemical sensing and analysis from molecules to complex samples. UltraIR is pretrained on approximately 60 million simulated IR spectra using spectral reconstruction, molecular fingerprint similarity alignment, and functional-group prediction, then adapted to downstream objectives with task-specific labels or targets. Across functional-group prediction, molecular structure elucidation, physicochemical property prediction, mixture-component identification and quantification, bacterial classification, medicinal-herb geographic origin traceability and constituent quantification, microplastics classification, and soil property prediction, UltraIR outperforms conventional machine-learning and task-specific deep-learning baselines. It performs strongly with limited labeled experimental spectra and in zero-shot inference for the same analytical task across Fourier-transform infrared spectrometers and laboratories, providing a route to adaptable, data-efficient chemical sensing from complex real-world samples.

cs.LG↗

arXiv2026

scMIR: a vision-language foundation model for single-cell light microscopy image representation

Single-cell light microscopy images have become an important data source for characterizing cell phenotypes, but their complexity and heterogeneity pose challenges to high-throughput automated analysis. Existing representation learning methods mostly rely on task-oriented modeling, which is limited by specific datasets and predefined tasks, making them difficult to generalize across different cell types and microscopy modalities, and experimental conditions. Although general-purpose methods have improved the generalization ability of image representation in recent years, their limited utilization of experimental background and biological context information still poses challenges in complex phenotypic analysis. Here, we propose scMIR, a vision-language foundation model for single-cell light microscopy image representation. By synergistically combining self-supervised image reconstruction with text-guided cross-modal alignment, scMIR can simultaneously encode morphological and biological semantic information in a unified representation space. scMIR is pre-trained on 207,957 image-text pairs, covering various cell types, microscopy modalities, and perturbation conditions. scMIR outperforms existing general models and task-oriented methods as systematically evaluated on various complex tasks using 16 benchmark datasets, including cell classification, clustering, phenotype inference, and batch effect correction tasks. Furthermore, scMIR shows a strong generalization ability across various tasks without requiring task-specific fine-tuning. With its unique advantages, we envision scMIR may promote the standardization and automation of high-throughput phenotyping workflows through supporting various downstream analysis tasks.

cs.CV↗

arXiv2026

A large-scale foundation model enables simulation-to-real adaptation for nuclear magnetic resonance-based molecular structure analysis

Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful tool for molecular structure analysis, and spectral artificial intelligence offers great potential for its rapid and automated interpretation. However, the scarcity of experimental NMR datasets has constrained deep learning in this domain to narrow, task-specific applications that lack broad generalization. Here, we introduce UltraNMR, a large-scale foundation model for NMR that leverages the intrinsic properties of NMR spectra to learn generalizable spectral representations. We collected 158 million paired simulated $^{1}$H and $^{13}$C NMR spectra to train UltraNMR, employing multiple domain-specific pre-training objectives. UltraNMR captures both intra-spectral and inter-spectral dependencies, enabling seamless simulation-to-real adaptation. We demonstrate that adapting UltraNMR to a range of molecular structure analysis tasks on experimental NMR spectra consistently yields state-of-the-art performance and clearly outperforms UltraNMR variants trained directly on downstream data without simulation pre-training. We also construct a large-scale NMR spectral vector library by encoding simulated NMR spectra using UltraNMR, covering 94 million unique molecules and enabling effective structure-aware retrieval. In real-world applications, UltraNMR facilitates the structural elucidation of two previously unknown natural products from Chinese herbal medicines recorded in the Chinese Pharmacopoeia. These results suggest that large-scale simulation pre-training can effectively bridge the simulation-to-real gap, enabling robust and generalizable molecular structure analysis of real-world NMR spectra.

physics.chem-ph↗

arXiv2026

Rethinking Genomic Modeling Through Optical Character Recognition

Recent genomic foundation models largely adopt large language model architectures that treat DNA as a one-dimensional token sequence. However, exhaustive sequential reading is structurally misaligned with sparse and discontinuous genomic semantics, leading to wasted computation on low-information background and preventing understanding-driven compression for long contexts. Here, we present OpticalDNA, a vision-based framework that reframes genomic modeling as Optical Character Recognition (OCR)-style document understanding. OpticalDNA renders DNA into structured visual layouts and trains an OCR-capable vision--language model with a visual DNA encoder and a document decoder, where the encoder produces compact, reconstructible visual tokens for high-fidelity compression. Building on this representation, OpticalDNA defines prompt-conditioned objectives over core genomic primitives-reading, region grounding, subsequence retrieval, and masked span completion-thereby learning layout-aware DNA representations that retain fine-grained genomic information under a reduced effective token budget. Across diverse genomic benchmarks, OpticalDNA consistently outperforms recent baselines; on sequences up to 450k bases, it achieves the best overall performance with nearly 20$\times$ fewer effective tokens, and surpasses models with up to 985$\times$ more activated parameters while tuning only 256k trainable parameters.

cs.CV↗

arXiv2026

CryoProt: A Protein Pretraining Framework with Cross-Box Interactions on Cryo-EM Density Maps

Despite the growing availability of cryo-electron microscopy (cryo-EM) density maps, effectively leveraging them for protein representation remains challenging. First, current methods lack a general-purpose protein pretraining framework tailored for cryo-EM density maps, designed for protein-related property prediction. Second, existing approaches typically partition density maps into local box regions and model them independently, overlooking interactions across boxes which are essential for capturing global structural context in cryo-EM density map. To address these challenges, we propose CryoProt, a protein pretraining framework designed for cryo-EM density maps. CryoProt introduces a Map Encoder based on multi-head latent attention (MLA), where box-level representations interact through a shared latent space, enabling explicit modeling of cross-box dependencies within the density map. Furthermore, we adopt a multi-task pretraining strategy to learn generalizable representations that can be effectively transferred to diverse downstream tasks, such as protein flexibility prediction, where cryo-EM density maps are not required and can be inferred implicitly by the pretrained model. Experimental results demonstrate that CryoProt consistently outperforms existing state-of-the-art methods across multiple benchmarks, achieving up to 12% improvement over the best-performing baselines, highlighting the importance of modeling cross-box interactions in cryo-EM data. The source code is publicly available at https://anonymous.4open.science/r/CryoProt.

cs.LG↗

arXiv2026

Property Enhanced Instruction Tuning for Multi-task Molecule Generation with Large Language Models

Large language models (LLMs) are widely applied in various natural language processing tasks such as question answering and machine translation. However, due to the lack of labeled data and the difficulty of manual annotation for biochemical properties, the performance for molecule generation tasks is still limited, especially for tasks involving multi-properties constraints. In this work, we present a two-step framework PEIT (\textbf{P}roperty \textbf{E}nhanced \textbf{I}nstruction \textbf{T}uning) to improve LLMs for molecular-related tasks. In the first step, we use textual descriptions, SMILES, and biochemical properties as multimodal inputs to pre-train a model called PEIT-GEN, by aligning multi-modal representations to synthesize instruction data. In the second step, we fine-tune existing open-source LLMs with the synthesized data, the resulting PEIT-LLM can handle molecule captioning, text-based molecule generation, molecular property prediction, and our newly proposed multi-constraint molecule generation tasks. Experimental results show that our pre-trained PEIT-GEN outperforms MolT5, BioT5, MolCA and Text+Chem-T5 in molecule captioning, demonstrating modalities align well between textual descriptions, structures, and biochemical properties. Furthermore, PEIT-LLM shows promising improvements in multi-task molecule generation, demonstrating the effectiveness of the PEIT framework for molecular tasks. The code and appendix are available at https://github.com/chenlong164/PEIT.

cs.AI↗

arXiv2026

SurfDesign: Effective Protein Design on Molecular Surfaces

Protein function is largely determined by molecular surface geometry and physicochemical complementarity, yet most protein design methods condition only on backbone structure. We introduce SurfDesign, a surface-conditioned protein design framework that models molecular surfaces as continuous geometric manifolds and integrates them with pretrained protein language models. SurfDesign employs surface-based equivariant message passing to capture surface normals, curvature, and directional geometry, together with a parameter-efficient fine-tuning strategy. Focusing on functional protein design, we show that SurfDesign consistently outperforms prior surface-conditioned and backbone-only methods on de novo binder and enzyme design benchmarks. We also report strong performance on inverse-folding benchmarks as a diagnostic of structural compatibility. Our results highlight manifold-aware surface representations as a principled foundation for functional protein and enzyme design. Code is available at https://github.com/smiles724/SurfDesign.

q-bio.BM↗

arXiv2026

CaptchaMind: Training CAPTCHA Solvers via Reinforcement Learning with Explicit Reasoning Supervision

CAPTCHAs are widely deployed as human verification mechanisms and frequently block intelligent agents from completing end-to-end automation in real-world web environments. Solving modern CAPTCHAs requires robust multi-step visual reasoning and interaction capabilities, yet training-based approaches have remained absent due to the lack of large-scale training data and process-level annotations. We introduce CaptchaBench, the first CAPTCHA benchmark designed to support large-scale training, comprising 16,000 programmatically generated samples across eight task categories with detailed region and process-level annotations. Systematic evaluation on CaptchaBench reveals that existing methods fail consistently on tasks requiring fine-grained visual detail capture and region-level comparison. We therefore present CaptchaMind, an RL-based solver trained with explicit reasoning process supervision, achieving 82.9% average success rate across eight tasks and 71.0% on real-world instances, substantially outperforming all existing methods without closed-source APIs.

cs.CV↗

arXiv2026

SpecX: A Large-Scale Benchmark for Multi-Modal Spectroscopy and Cross-Paradigm Evaluation

Existing spectral benchmarks are limited in scale, modality alignment, and evaluation scope, and typically focus on either specialized models or multimodal language models (MLLMs). We introduce SpecX, a large-scale benchmark for multi-modal spectroscopy with cross-paradigm evaluation. SpecX contains 1.7M molecules with diverse spectral modalities, including NMR (1H, 13C, HSQC), IR, MS,UV,Raman and FL, and is organized into three tiers: a large-scale dataset for pretraining, an aligned multi-spectral subset for benchmarking, and a high-quality experimental subset for evaluation. SpecX supports a range of tasks such as molecular elucidation, spectrum simulation, and spectral understanding, and enables unified evaluation across both specialized spectral models and MLLMs. Experiments show that specialized models excel at signal-level modeling, while MLLMs exhibit strengths in high-level reasoning but lack precise spectral grounding. SpecX establishes a unified benchmark for spectral intelligence and highlights the need for spectrum-native foundation models.

eess.IV↗

arXiv2026

Agents on a Tree: Pathwise Coordination for Multi-Objective Molecular Optimization

Multi-objective molecular optimization requires searching vast chemical spaces under conflicting objectives, where early design decisions strongly constrain downstream outcomes. Existing methods typically rely on a single policy or fixed scalarization, which limits their ability to represent diverse trade-offs and to explore multiple promising design trajectories. We propose ATOM, a multi-agent framework that formulates molecular optimization as a tree-structured search. Each node corresponds to an atomic operation and hosts an agent specialized for a particular objective or decision context. Agents coordinate along different paths of the tree rather than enforcing a global consensus, enabling the method to maintain and compare alternative molecular evolution trajectories. A global memory of past optimization behaviors further supports balanced exploration and exploitation across objectives. This tree-structured interaction enables reasoning over long-horizon dependencies inherent in molecular design. Experiments on challenging multi-objective benchmarks involving activity, synthesizability, and ADMET-related properties show that ATOM consistently achieves improved Pareto coverage and hypervolume over strong baselines. These results demonstrate the effectiveness of pathwise multi-agent coordination for molecular optimization. Code is available at https://anonymous.4open.science/r/ATOM-41CE.

cs.AI↗

arXiv2026

Sparse Task Vector Mixup with Hypernetworks for Efficient Knowledge Transfer in Whole-Slide Image Prognosis

Whole-Slide Images (WSIs) are widely used for estimating the prognosis of cancer patients. Current studies generally follow a cancer-specific learning paradigm. However, the available training samples for one cancer type are usually scarce in pathology. Consequently, the model often struggles to learn generalizable knowledge, thus performing worse on the tumor samples with inherent high heterogeneity. Although multi-cancer joint learning and knowledge transfer approaches have been explored recently to address it, they either rely on large-scale joint training or extensive inference across multiple models, posing new challenges in computational efficiency. To this end, this paper proposes a new scheme, Sparse Task Vector Mixup with Hypernetworks (STEPH). Unlike previous ones, it efficiently absorbs generalizable knowledge from other cancers for the target via model merging: i) applying task vector mixup to each source-target pair and then ii) sparsely aggregating task vector mixtures to obtain an improved target model, driven by hypernetworks. Extensive experiments on 13 cancer datasets show that STEPH improves over cancer-specific learning and an existing knowledge transfer baseline by 5.14% and 2.01%, respectively. Moreover, it is a more efficient solution for learning prognostic knowledge from other cancers, without requiring large-scale joint training or extensive multi-model inference. Code is publicly available at https://github.com/liupei101/STEPH.

cs.CV↗

arXiv2026

DyACE: Dynamic Algorithm Co-evolution for Online Automated Heuristic Design with Large Language Model

The prevailing paradigm in Automated Heuristic Design (AHD) typically relies on the assumption that a single, fixed algorithm can effectively navigate the shifting dynamics of a combinatorial search. This static approach often proves inadequate for Perturbative Heuristics, where the optimal algorithm for escaping local optima depends heavily on the specific search phase. To address this limitation, we reformulate heuristic design as a Non-stationary Bi-level Control problem and introduce DyACE (Dynamic Algorithm Co-evolution). Distinct from standard open-loop solvers, DyACE use a Receding Horizon Control architecture to continuously co-evolve the heuristic logic alongside the solution population. A core element of this framework is the Look-Ahead Rollout Search, which queries the landscape geometry to extract Search Trajectory Features. This sensory feedback allows the Large Language Model (LLM) to function as a grounded meta-controller, prescribing phase-specific interventions tailored to the real-time search status. We validate DyACE on three representative combinatorial optimization benchmarks. The results demonstrate that our method significantly outperforms state-of-the-art static baselines, exhibiting superior scalability in high-dimensional search spaces. Furthermore, ablation studies confirm that dynamic adaptation fails without grounded perception, often performing worse than static algorithms. This indicates that DyACE's effectiveness stems from the causal alignment between the synthesized logic and the verified gradients of the optimization landscape.

cs.AI↗

arXiv2026

Surface-based Molecular Design with Multi-modal Flow Matching

Therapeutic peptides show promise in targeting previously undruggable binding sites, with recent advancements in deep generative models enabling full-atom peptide co-design for specific protein receptors. However, the critical role of molecular surfaces in protein-protein interactions (PPIs) has been underexplored. To bridge this gap, we propose an omni-design peptides generation paradigm, called SurfFlow, a novel surface-based generative algorithm that enables comprehensive co-design of sequence, structure, and surface for peptides. SurfFlow employs a multi-modality conditional flow matching (CFM) architecture to learn distributions of surface geometries and biochemical properties, enhancing peptide binding accuracy. Evaluated on the comprehensive PepMerge benchmark, SurfFlow consistently outperforms full-atom baselines across all metrics. These results highlight the advantages of considering molecular surfaces in de novo peptide discovery and demonstrate the potential of integrating multiple protein modalities for more effective therapeutic peptide discovery.

cs.LG↗

arXiv2025

Cross-Cancer Knowledge Transfer in WSI-based Prognosis Prediction

Whole-Slide Image (WSI) is an important tool for estimating cancer prognosis. Current studies generally follow a conventional cancer-specific paradigm in which each cancer corresponds to a single model. However, this paradigm naturally struggles to scale to rare tumors and cannot leverage knowledge from other cancers. While multi-task learning frameworks have been explored recently, they often place high demands on computational resources and require extensive training on ultra-large, multi-cancer WSI datasets. To this end, this paper shifts the paradigm to knowledge transfer and presents the first preliminary yet systematic study on cross-cancer prognosis knowledge transfer in WSIs, called CROPKT. It comprises three major parts. (1) We curate a large dataset (UNI2-h-DSS) with 26 cancers and use it to measure the transferability of WSI-based prognostic knowledge across different cancers (including rare tumors). (2) Beyond a simple evaluation merely for benchmarking, we design a range of experiments to gain deeper insights into the underlying mechanism behind transferability. (3) We further show the utility of cross-cancer knowledge transfer, by proposing a routing-based baseline approach (ROUPKT) that could often efficiently utilize the knowledge transferred from off-the-shelf models of other cancers. CROPKT could serve as an inception that lays the foundation for this nascent paradigm, i.e., WSI-based prognosis prediction with cross-cancer knowledge transfer. Our source code is available at https://github.com/liupei101/CROPKT.

eess.IV↗

arXiv2025

DeepDR: an integrated deep-learning model web server for drug repositioning

Background: Identifying new indications for approved drugs is a complex and time-consuming process that requires extensive knowledge of pharmacology, clinical data, and advanced computational methods. Recently, deep learning (DL) methods have shown their capability for the accurate prediction of drug repositioning. However, implementing DL-based modeling requires in-depth domain knowledge and proficient programming skills. Results: In this application, we introduce DeepDR, the first integrated platform that combines a variety of established DL-based models for disease- and target-specific drug repositioning tasks. DeepDR leverages invaluable experience to recommend candidate drugs, which covers more than 15 networks and a comprehensive knowledge graph that includes 5.9 million edges across 107 types of relationships connecting drugs, diseases, proteins/genes, pathways, and expression from six existing databases and a large scientific corpus of 24 million PubMed publications. Additionally, the recommended results include detailed descriptions of the recommended drugs and visualize key patterns with interpretability through a knowledge graph. Conclusion: DeepDR is free and open to all users without the requirement of registration. We believe it can provide an easy-to-use, systematic, highly accurate, and computationally automated platform for both experimental and computational scientists.

cs.LG↗

arXiv2025

From Knowledge to Treatment: Large Language Model Assisted Biomedical Concept Representation for Drug Repurposing

Drug repurposing plays a critical role in accelerating treatment discovery, especially for complex and rare diseases. Biomedical knowledge graphs (KGs), which encode rich clinical associations, have been widely adopted to support this task. However, existing methods largely overlook common-sense biomedical concept knowledge in real-world labs, such as mechanistic priors indicating that certain drugs are fundamentally incompatible with specific treatments. To address this gap, we propose LLaDR, a Large Language Model-assisted framework for Drug Repurposing, which improves the representation of biomedical concepts within KGs. Specifically, we extract semantically enriched treatment-related textual representations of biomedical entities from large language models (LLMs) and use them to fine-tune knowledge graph embedding (KGE) models. By injecting treatment-relevant knowledge into KGE, LLaDR largely improves the representation of biomedical concepts, enhancing semantic understanding of under-studied or complex indications. Experiments based on benchmarks demonstrate that LLaDR achieves state-of-the-art performance across different scenarios, with case studies on Alzheimer's disease further confirming its robustness and effectiveness. Code is available at https://github.com/xiaomingaaa/LLaDR.

cs.CL↗

arXiv2025

Enhancing Molecular Property Prediction with Knowledge from Large Language Models

Predicting molecular properties is a critical component of drug discovery. Recent advances in deep learning, particularly Graph Neural Networks (GNNs), have enabled end-to-end learning from molecular structures, reducing reliance on manual feature engineering. However, while GNNs and self-supervised learning approaches have advanced molecular property prediction (MPP), the integration of human prior knowledge remains indispensable, as evidenced by recent methods that leverage large language models (LLMs) for knowledge extraction. Despite their strengths, LLMs are constrained by knowledge gaps and hallucinations, particularly for less-studied molecular properties. In this work, we propose a novel framework that, for the first time, integrates knowledge extracted from LLMs with structural features derived from pre-trained molecular models to enhance MPP. Our approach prompts LLMs to generate both domain-relevant knowledge and executable code for molecular vectorization, producing knowledge-based features that are subsequently fused with structural representations. We employ three state-of-the-art LLMs, GPT-4o, GPT-4.1, and DeepSeek-R1, for knowledge extraction. Extensive experiments demonstrate that our integrated method outperforms existing approaches, confirming that the combination of LLM-derived knowledge and structural information provides a robust and effective solution for MPP.

cs.CL↗