Yikun Zhang

Ken Gu, Ruoxi Shang, Ruien Jiang et al. · uw

Data-driven scientific discovery requires the iterative integration of scientific domain knowledge, statistical expertise, and an understanding of data semantics to make nuanced analytical decisions, e.g., about which variables, transformations, and statistical models to consider. LM-based agents equipped with planning, memory, and code execution capabilities have the potential to support data-driven science. However, evaluating agents on such open-ended tasks is challenging due to multiple valid approaches, partially correct steps, and different ways to express the same decisions. To address these challenges, we present BLADE, a benchmark to automatically evaluate agents' multifaceted approaches to open-ended research questions. BLADE consists of 12 datasets and research questions drawn from existing scientific literature, with ground truth collected from independent analyses by expert data scientists and researchers. To automatically evaluate agent responses, we developed corresponding computational methods to match different representations of analyses to this ground truth. Though language models possess considerable world knowledge, our evaluation shows that they are often limited to basic analyses. However, agents capable of interacting with the underlying data demonstrate improved, but still non-optimal, diversity in their analytical decision making. Our work enables the evaluation of agents for data-driven science and provides researchers deeper insights into agents' analysis approaches.

Bin Huang, Xun Yu, Yikun Zhang et al.

Low-dose computed tomography (LDCT) reconstruction is fundamentally challenged by severe noise and compromised data fidelity under reduced radiation exposure. Most existing methods operate either in the image or post-log projection domain, which fails to fully exploit the rich structural information in pre-log measurements while being highly susceptible to noise. The requisite logarithmic transformation critically amplifies noise within these data, imposing exceptional demands on reconstruction precision. To overcome these challenges, we propose PLOT-CT, a novel framework for Pre-Log vOronoi decomposiTion-assisted CT generation. Our method begins by applying Voronoi decomposition to pre-log sinograms, disentangling the data into distinct underlying components, which are embedded in separate latent spaces. This explicit decomposition significantly enhances the model's capacity to learn discriminative features, directly improving reconstruction accuracy by mitigating noise and preserving information inherent in the pre-log domain. Extensive experiments demonstrate that PLOT-CT achieves state-of-the-art performance, attaining a 2.36dB PSNR improvement over traditional methods at the 1e4 incident photon level in the pre-log domain.

Yuanqi Du, Botao Yu, Tianyu Liu et al.

There has been unprecedented interest in developing agents that expand the boundary of scientific discovery, primarily by optimizing quantitative objective functions specified by scientists. However, for grand challenges in science , these objectives are only imperfect proxies. We argue that automating objective function design is a central, yet unmet requirement for scientific discovery agents. In this work, we introduce the Scientific Autonomous Goal-evolving Agent (SAGA) to amend this challenge. SAGA employs a bi-level architecture in which an outer loop of LLM agents analyzes optimization outcomes, proposes new objectives, and converts them into computable scoring functions, while an inner loop performs solution optimization under the current objectives. This bi-level design enables systematic exploration of the space of objectives and their trade-offs, rather than treating them as fixed inputs. We demonstrate the framework through a broad spectrum of applications, including antibiotic design, inorganic materials design, functional DNA sequence design, and chemical process design, showing that automating objective formulation can substantially improve the effectiveness of scientific discovery agents.

Yikun Zhang, Steven Wilkins-Reeves, Wesley Lee et al.

We introduce a transfer learning framework for regression that leverages heterogeneous source domains to improve predictive performance in a data-scarce target domain. Our approach learns a conditional generative model separately for each source domain and calibrates the generated responses to the target domain via conditional quantile matching. This distributional alignment step corrects general discrepancies between source and target domains without imposing restrictive assumptions such as covariate or label shift. The resulting framework provides a principled and flexible approach to high-quality data augmentation for downstream learning tasks in the target domain. From a theoretical perspective, we show that an empirical risk minimizer (ERM) trained on the augmented dataset achieves a tighter excess risk bound than the target-only ERM under mild conditions. In particular, we establish new convergence rates for the quantile matching estimator that governs the transfer bias-variance tradeoff. From a practical perspective, extensive simulations and real data applications demonstrate that the proposed method consistently improves prediction accuracy over target-only learning and competing transfer learning methods.

Yikun Zhang, Geyan Ye, Chaohao Yuan et al.

Molecule-and-text cross-modal representation learning has emerged as a promising direction for enhancing the quality of molecular representation, thereby improving performance in various scientific fields. However, most approaches employ a global alignment approach to learn the knowledge from different modalities that may fail to capture fine-grained information, such as molecule-and-text fragments and stereoisomeric nuances, which is crucial for downstream tasks. Furthermore, it is incapable of modeling such information using a similar global alignment strategy due to the lack of annotations about the fine-grained fragments in the existing dataset. In this paper, we propose Atomas, a hierarchical molecular representation learning framework that jointly learns representations from SMILES strings and text. We design a Hierarchical Adaptive Alignment model to automatically learn the fine-grained fragment correspondence between two modalities and align these representations at three semantic levels. Atomas's end-to-end training framework supports understanding and generating molecules, enabling a wider range of downstream tasks. Atomas achieves superior performance across 12 tasks on 11 datasets, outperforming 11 baseline models thus highlighting the effectiveness and versatility of our method. Scaling experiments further demonstrate Atomas's robustness and scalability. Moreover, visualization and qualitative analysis, validated by human experts, confirm the chemical relevance of our approach. Codes are released on https://github.com/yikunpku/Atomas.

Yikun Zhang, Xiwei Cheng, Tianyu Liu et al.

Building state-of-the-art (SOTA) predictive models for drug discovery requires expensive search over tools, architectures, and training strategies. Current LLM-based agents can find SOTA solutions through extensive trial and error, but they do not retain the experience accumulated along the way and therefore pay the full search cost on every new task. We propose \method (Self-evolving Agent Experience), a framework that accumulates and reuses experience across tasks to build SOTA drug discovery models efficiently. \method maintains a cross-task memory of verified skills, statistical evidence about effective strategies, and a record of recurring errors and their fixes. In some cases, \method transfers a working solution directly without test-time search. In 33 molecular property prediction tasks, \method ranks first among nine SOTA agents in a single-task setting. With memory accumulated from 16 smaller tasks, \method achieves an averaged normalized score of 0.935 on 17 held-out tasks in a cross-task evaluation setting and outperforms all baseline agents by 10-30\% in a zero-test-time search regime. In summary, our work shows the advantage of cross-task memory for efficient SOTA model development in drug discovery.

Jian Lin, Jiancheng Fang, Shaoyu Wang et al.

While 3D Gaussian splatting (3DGS) offers explicit and efficient scene representations for cone-beam computed tomography reconstruction, conventional photometric optimization inherently suffers from spectral bias under ultra sparse-view conditions, leading to over-smoothing and a loss of high-frequency anatomical details. Since wavelet transforms provide rich high-frequency information and have been widely utilized to enhance sparse reconstruction, this work integrates wavelet multi-resolution analysis with 3DGS. To circumvent the mathematical mismatch between the strict non-negativity of physical X-ray attenuation and the bipolar nature of high-frequency wavelet coefficients, we propose Residual Gaussian Splatting (RGS). Methodologically, we introduce a spectrally-decoupled Gaussian representation that stratifies the volumetric field into a geometric base component and a residual detail component. This decomposition systematically transforms explicit high-frequency fitting into a physically consistent, implicit residual compensation task. Furthermore, we devise a spectral-spatial collaborative optimization strategy to coordinate the interplay between geometric anchoring and texture refinement, effectively preventing spectral crosstalk. Extensive experiments on clinical datasets demonstrate that RGS enables the reconstructed images to capture highly refined geometric textures. It successfully resolves the trade-off between artifact suppression and detail preservation, yielding superior visual fidelity in complex trabecular and vascular structures compared to existing neural rendering baselines.

Chaohao Yuan, Songyou Li, Geyan Ye et al.

The core challenge of de novo protein design lies in creating proteins with specific functions or properties, guided by certain conditions. Current models explore to generate protein using structural and evolutionary guidance, which only provide indirect conditions concerning functions and properties. However, textual annotations of proteins, especially the annotations for protein domains, which directly describe the protein's high-level functionalities, properties, and their correlation with target amino acid sequences, remain unexplored in the context of protein design tasks. In this paper, we propose Protein-Annotation Alignment Generation, PAAG, a multi-modality protein design framework that integrates the textual annotations extracted from protein database for controllable generation in sequence space. Specifically, within a multi-level alignment module, PAAG can explicitly generate proteins containing specific domains conditioned on the corresponding domain annotations, and can even design novel proteins with flexible combinations of different kinds of annotations. Our experimental results underscore the superiority of the aligned protein representations from PAAG over 7 prediction tasks. Furthermore, PAAG demonstrates a significant increase in generation success rate (24.7% vs 4.7% in zinc finger, and 54.3% vs 22.0% in the immunoglobulin domain) in comparison to the existing model. We anticipate that PAAG will broaden the horizons of protein design by leveraging the knowledge from between textual annotation and proteins.

He Wang, Yikun Zhang, Jie Chen et al.

Given usefulness of protein language models (LMs) in structure and functional inference, RNA LMs have received increased attentions in the last few years. However, these RNA models are often not compared against the same standard. Here, we divided RNA LMs into three classes (pretrained on multiple RNA types (especially noncoding RNAs), specific-purpose RNAs, and LMs that unify RNA with DNA or proteins or both) and compared 13 RNA LMs along with 3 DNA and 1 protein LMs as controls in zero-shot prediction of RNA secondary structure and functional classification. Results shows that the models doing well on secondary structure prediction often perform worse in function classification or vice versa, suggesting that more balanced unsupervised training is needed.

Jiancheng Fang, Shaoyu Wang, Junlin Wang et al.

Multi-source stationary computed tomography (CT) has recently attracted attention for its ability to achieve rapid image reconstruction, making it suitable for time-sensitive clinical and industrial applications. However, practical systems are often constrained by ultra-sparse-view sampling, which significantly degrades reconstruction quality. Traditional methods struggle under ultra-sparse-view settings, where interpolation becomes inaccurate and the resulting reconstructions are unsatisfactory. To address this challenge, this study proposes Diffusion-Refined Neural Attenuation Fields (Diff-NAF), an iterative framework tailored for multi-source stationary CT under ultra-sparse-view conditions. Diff-NAF combines a Neural Attenuation Field representation with a dual-branch conditional diffusion model. The process begins by training an initial NAF using ultra-sparse-view projections. New projections are then generated through an Angle-Prior Guided Projection Synthesis strategy that exploits inter view priors, and are subsequently refined by a Diffusion-driven Reuse Projection Refinement Module. The refined projections are incorporated as pseudo-labels into the training set for the next iteration. Through iterative refinement, Diff-NAF progressively enhances projection completeness and reconstruction fidelity under ultra-sparse-view conditions, ultimately yielding high-quality CT reconstructions. Experimental results on multiple simulated 3D CT volumes and real projection data demonstrate that Diff-NAF achieves the best performance under ultra-sparse-view conditions.

Siyuan Chen, Minghao Guo, Caoliwen Wang et al.

Biomolecular interaction modeling has been substantially advanced by foundation models, yet they often produce all-atom structures that violate basic steric feasibility. We address this limitation by enforcing physical validity as a strict constraint during both training and inference with a uniffed module. At its core is a differentiable projection that maps the provisional atom coordinates from the diffusion model to the nearest physically valid conffguration. This projection is achieved using a Gauss-Seidel scheme, which exploits the locality and sparsity of the constraints to ensure stable and fast convergence at scale. By implicit differentiation to obtain gradients, our module integrates seamlessly into existing frameworks for end-to-end ffnetuning. With our Gauss-Seidel projection module in place, two denoising steps are sufffcient to produce biomolecular complexes that are both physically valid and structurally accurate. Across six benchmarks, our 2-step model achieves the same structural accuracy as state-of-the-art 200-step diffusion baselines, delivering approximately 10 times faster wall-clock speed while guaranteeing physical validity.

Yikun Zhang, Yen-Chi Chen

The set of local modes and density ridge lines are important summary characteristics of the data-generating distribution. In this work, we focus on estimating local modes and density ridges from point cloud data in a product space combining two or more Euclidean and/or directional metric spaces. Specifically, our approach extends the (subspace constrained) mean shift algorithm to such product spaces, addressing potential challenges in the generalization process. We establish the algorithmic convergence of the proposed methods, along with practical implementation guidelines. Experiments on simulated and real-world datasets demonstrate the effectiveness of our proposed methods.

Yikun Zhang, Yen-Chi Chen

This paper studies the linear convergence of the subspace constrained mean shift (SCMS) algorithm, a well-known algorithm for identifying a density ridge defined by a kernel density estimator. By arguing that the SCMS algorithm is a special variant of a subspace constrained gradient ascent (SCGA) algorithm with an adaptive step size, we derive the linear convergence of such SCGA algorithm. While the existing research focuses mainly on density ridges in the Euclidean space, we generalize density ridges and the SCMS algorithm to directional data. In particular, we establish the stability theorem of density ridges with directional data and prove the linear convergence of our proposed directional SCMS algorithm.

Yikun Zhang, Yen-Chi Chen

The directional mean shift (DMS) algorithm is a nonparametric method for pursuing local modes of densities defined by kernel density estimators on the unit hypersphere. In this paper, we show that any DMS iteration can be viewed as a generalized Expectation-Maximization (EM) algorithm; in particular, when the von Mises kernel is applied, it becomes an exact EM algorithm. Under the (generalized) EM framework, we provide a new proof for the ascending property of density estimates and demonstrate the global convergence of directional mean shift sequences. Finally, we give a new insight into the linear convergence of the DMS algorithm.

Yikun Zhang, Yen-Chi Chen

Directional data consist of observations distributed on a (hyper)sphere, and appear in many applied fields, such as astronomy, ecology, and environmental science. This paper studies both statistical and computational problems of kernel smoothing for directional data. We generalize the classical mean shift algorithm to directional data, which allows us to identify local modes of the directional kernel density estimator (KDE). The statistical convergence rates of the directional KDE and its derivatives are derived, and the problem of mode estimation is examined. We also prove the ascending property of the directional mean shift algorithm and investigate a general problem of gradient ascent on the unit hypersphere. To demonstrate the applicability of the algorithm, we evaluate it as a mode clustering method on both simulated and real-world data sets.

Zhuonan He, Yikun Zhang, Yu Guan et al.

Dose reduction in computed tomography (CT) is essential for decreasing radiation risk in clinical applications. Iterative reconstruction is one of the most promising ways to compensate for the increased noise due to reduction of photon flux. Rather than most existing prior-driven algorithms that benefit from manually designed prior functions or supervised learning schemes, in this work we integrate the data-consistency as a conditional term into the iterative generative model for low-dose CT. At the stage of prior learning, the gradient of data density is directly learned from normal-dose CT images as a prior. Then at the iterative reconstruction stage, the stochastic gradient descent is employed to update the trained prior with annealed and conditional schemes. The distance between the reconstructed image and the manifold is minimized along with data fidelity during reconstruction. Experimental comparisons demonstrated the noise reduction and detail preservation abilities of the proposed method.