Xiner Li

Xuan Zhang, Limei Wang, Jacob Helwig et al. · cambridge, mit

Advances in artificial intelligence (AI) are fueling a new paradigm of discoveries in natural sciences. Today, AI has started to advance natural sciences by improving, accelerating, and enabling our understanding of natural phenomena at a wide range of spatial and temporal scales, giving rise to a new area of research known as AI for science (AI4Science). Being an emerging research paradigm, AI4Science is unique in that it is an enormous and highly interdisciplinary area. Thus, a unified and technical treatment of this field is needed yet challenging. This work aims to provide a technically thorough account of a subarea of AI4Science; namely, AI for quantum, atomistic, and continuum systems. These areas aim at understanding the physical world from the subatomic (wavefunctions and electron density), atomic (molecules, proteins, materials, and interactions), to macro (fluids, climate, and subsurface) scales and form an important subarea of AI4Science. A unique advantage of focusing on these areas is that they largely share a common set of challenges, thereby allowing a unified and foundational treatment. A key common challenge is how to capture physics first principles, especially symmetries, in natural systems by deep learning methods. We provide an in-depth yet intuitive account of techniques to achieve equivariance to symmetry transformations. We also discuss other common technical challenges, including explainability, out-of-distribution generalization, knowledge transfer with foundation and large language models, and uncertainty quantification. To facilitate learning and education, we provide categorized lists of resources that we found to be useful. We strive to be thorough and unified and hope this initial effort may trigger more community interests and efforts to further advance AI4Science.

Shurui Gui, Xiner Li, Limei Wang et al.

Out-of-distribution (OOD) learning deals with scenarios in which training and test data follow different distributions. Although general OOD problems have been intensively studied in machine learning, graph OOD is only an emerging area of research. Currently, there lacks a systematic benchmark tailored to graph OOD method evaluation. In this work, we aim at developing an OOD benchmark, known as GOOD, for graphs specifically. We explicitly make distinctions between covariate and concept shifts and design data splits that accurately reflect different shifts. We consider both graph and node prediction tasks as there are key differences in designing shifts. Overall, GOOD contains 11 datasets with 17 domain selections. When combined with covariate, concept, and no shifts, we obtain 51 different splits. We provide performance results on 10 commonly used baseline methods with 10 random runs. This results in 510 dataset-model combinations in total. Our results show significant performance gaps between in-distribution and OOD settings. Our results also shed light on different performance trends between covariate and concept shifts by different methods. Our GOOD benchmark is a growing project and expects to expand in both quantity and variety of resources as the area develops. The GOOD benchmark can be accessed via https://github.com/divelab/GOOD/.

Xiner Li, Yulai Zhao, Chenyu Wang et al. · princeton

Diffusion models excel at capturing the natural design spaces of images, molecules, DNA, RNA, and protein sequences. However, rather than merely generating designs that are natural, we often aim to optimize downstream reward functions while preserving the naturalness of these design spaces. Existing methods for achieving this goal often require ``differentiable'' proxy models (\textit{e.g.}, classifier guidance or DPS) or involve computationally expensive fine-tuning of diffusion models (\textit{e.g.}, classifier-free guidance, RL-based fine-tuning). In our work, we propose a new method to address these challenges. Our algorithm is an iterative sampling method that integrates soft value functions, which looks ahead to how intermediate noisy states lead to high rewards in the future, into the standard inference procedure of pre-trained diffusion models. Notably, our approach avoids fine-tuning generative models and eliminates the need to construct differentiable models. This enables us to (1) directly utilize non-differentiable features/reward feedback, commonly used in many scientific domains, and (2) apply our method to recent discrete diffusion models in a principled way. Finally, we demonstrate the effectiveness of our algorithm across several domains, including image generation, molecule generation, and DNA/RNA sequence generation. The code is available at \href{https://github.com/masa-ue/SVDD}{https://github.com/masa-ue/SVDD}.

Shurui Gui, Meng Liu, Xiner Li et al.

We tackle the problem of graph out-of-distribution (OOD) generalization. Existing graph OOD algorithms either rely on restricted assumptions or fail to exploit environment information in training data. In this work, we propose to simultaneously incorporate label and environment causal independence (LECI) to fully make use of label and environment information, thereby addressing the challenges faced by prior methods on identifying causal and invariant subgraphs. We further develop an adversarial training strategy to jointly optimize these two properties for causal subgraph discovery with theoretical guarantees. Extensive experiments and analysis show that LECI significantly outperforms prior methods on both synthetic and real-world datasets, establishing LECI as a practical and effective solution for graph OOD generalization. Our code is available at https://github.com/divelab/LECI.

Shubham Parashar, Shurui Gui, Xiner Li et al.

We aim to improve the reasoning capabilities of language models via reinforcement learning (RL). Recent RL post-trained models like DeepSeek-R1 have demonstrated reasoning abilities on mathematical and coding tasks. However, prior studies suggest that using RL alone to improve reasoning on inherently difficult tasks is less effective. Here, we draw inspiration from curriculum learning and propose to schedule tasks from easy to hard (E2H), allowing LLMs to build reasoning skills gradually. Our method is termed E2H Reasoner. Empirically, we observe that, although easy tasks are important initially, fading them out through appropriate scheduling is essential in preventing overfitting. Theoretically, we establish convergence guarantees for E2H Reasoner within an approximate policy iteration framework. We derive finite-sample complexity bounds and show that when tasks are appropriately decomposed and conditioned, learning through curriculum stages requires fewer total samples than direct learning. Experiments across multiple domains show that E2H Reasoner significantly improves the reasoning ability of small LLMs (1.5B to 3B), which otherwise struggle when trained with vanilla RL alone, highlighting the effectiveness of our method. Our code can be found on https://github.com/divelab/E2H-Reasoning.

Ziqi Wang, Hanlin Zhang, Xiner Li et al.

Position bias has proven to be a prevalent issue of modern language models (LMs), where the models prioritize content based on its position within the given context. This bias often leads to unexpected model failures and hurts performance, robustness, and reliability across various applications. Our mechanistic analysis attributes the position bias to two components employed in nearly all state-of-the-art LMs: causal attention and relative positional encodings. Based on the analyses, we propose to eliminate position bias (e.g., different retrieved documents' orders in QA affect performance) with a training-free zero-shot approach. Our method changes the causal attention to bidirectional attention between documents and utilizes model attention values to decide the relative orders of documents instead of using the order provided in input prompts, therefore enabling Position-INvariant inferencE (PINE) at the document level. By eliminating position bias, models achieve better performance and reliability in downstream tasks, including LM-as-a-judge, retrieval-augmented QA, molecule generation, and math reasoning. Notably, PINE is especially useful when adapting LMs for evaluating reasoning pairs: it consistently provides 8 to 10 percentage points performance gains, making Llama-3-70B-Instruct perform even better than GPT-4-0125-preview and GPT-4o-2024-08-06 on the RewardBench reasoning set.

Xiner Li, Shurui Gui, Youzhi Luo et al.

Out-of-distribution (OOD) generalization deals with the prevalent learning scenario where test distribution shifts from training distribution. With rising application demands and inherent complexity, graph OOD problems call for specialized solutions. While data-centric methods exhibit performance enhancements on many generic machine learning tasks, there is a notable absence of data augmentation methods tailored for graph OOD generalization. In this work, we propose to achieve graph OOD generalization with the novel design of non-Euclidean-space linear extrapolation. The proposed augmentation strategy extrapolates both structure and feature spaces to generate OOD graph data. Our design tailors OOD samples for specific shifts without corrupting underlying causal mechanisms. Theoretical analysis and empirical results evidence the effectiveness of our method in solving target shifts, showing substantial and constant improvements across various graph OOD tasks.

Yue Huang, Lichao Sun, Haoran Wang et al.

Large language models (LLMs), exemplified by ChatGPT, have gained considerable attention for their excellent natural language processing capabilities. Nonetheless, these LLMs present many challenges, particularly in the realm of trustworthiness. Therefore, ensuring the trustworthiness of LLMs emerges as an important topic. This paper introduces TrustLLM, a comprehensive study of trustworthiness in LLMs, including principles for different dimensions of trustworthiness, established benchmark, evaluation, and analysis of trustworthiness for mainstream LLMs, and discussion of open challenges and future directions. Specifically, we first propose a set of principles for trustworthy LLMs that span eight different dimensions. Based on these principles, we further establish a benchmark across six dimensions including truthfulness, safety, fairness, robustness, privacy, and machine ethics. We then present a study evaluating 16 mainstream LLMs in TrustLLM, consisting of over 30 datasets. Our findings firstly show that in general trustworthiness and utility (i.e., functional effectiveness) are positively related. Secondly, our observations reveal that proprietary LLMs generally outperform most open-source counterparts in terms of trustworthiness, raising concerns about the potential risks of widely accessible open-source LLMs. However, a few open-source LLMs come very close to proprietary ones. Thirdly, it is important to note that some LLMs may be overly calibrated towards exhibiting trustworthiness, to the extent that they compromise their utility by mistakenly treating benign prompts as harmful and consequently not responding. Finally, we emphasize the importance of ensuring transparency not only in the models themselves but also in the technologies that underpin trustworthiness. Knowing the specific trustworthy technologies that have been employed is crucial for analyzing their effectiveness.

Xiner Li, Limei Wang, Youzhi Luo et al.

We consider molecule generation in 3D space using language models (LMs), which requires discrete tokenization of 3D molecular geometries. Although tokenization of molecular graphs exists, that for 3D geometries is largely unexplored. Here, we attempt to bridge this gap by proposing the Geo2Seq, which converts molecular geometries into $SE(3)$-invariant 1D discrete sequences. Geo2Seq consists of canonical labeling and invariant spherical representation steps, which together maintain geometric and atomic fidelity in a format conducive to LMs. Our experiments show that, when coupled with Geo2Seq, various LMs excel in molecular geometry generation, especially in controlled generation tasks.

Masatoshi Uehara, Yulai Zhao, Chenyu Wang et al. · princeton

This tutorial provides an in-depth guide on inference-time guidance and alignment methods for optimizing downstream reward functions in diffusion models. While diffusion models are renowned for their generative modeling capabilities, practical applications in fields such as biology often require sample generation that maximizes specific metrics (e.g., stability, affinity in proteins, closeness to target structures). In these scenarios, diffusion models can be adapted not only to generate realistic samples but also to explicitly maximize desired measures at inference time without fine-tuning. This tutorial explores the foundational aspects of such inference-time algorithms. We review these methods from a unified perspective, demonstrating that current techniques -- such as Sequential Monte Carlo (SMC)-based guidance, value-based sampling, and classifier guidance -- aim to approximate soft optimal denoising processes (a.k.a. policies in RL) that combine pre-trained denoising processes with value functions serving as look-ahead functions that predict from intermediate states to terminal rewards. Within this framework, we present several novel algorithms not yet covered in the literature. Furthermore, we discuss (1) fine-tuning methods combined with inference-time techniques, (2) inference-time algorithms based on search algorithms such as Monte Carlo tree search, which have received limited attention in current research, and (3) connections between inference-time algorithms in language models and diffusion models. The code of this tutorial on protein design is available at https://github.com/masa-ue/AlignInversePro

Shurui Gui, Xiner Li, Shuiwang Ji

Test-time adaptation (TTA) addresses distribution shifts for streaming test data in unsupervised settings. Currently, most TTA methods can only deal with minor shifts and rely heavily on heuristic and empirical studies. To advance TTA under domain shifts, we propose the novel problem setting of active test-time adaptation (ATTA) that integrates active learning within the fully TTA setting. We provide a learning theory analysis, demonstrating that incorporating limited labeled test instances enhances overall performances across test domains with a theoretical guarantee. We also present a sample entropy balancing for implementing ATTA while avoiding catastrophic forgetting (CF). We introduce a simple yet effective ATTA algorithm, known as SimATTA, using real-time sample selection techniques. Extensive experimental results confirm consistency with our theoretical analyses and show that the proposed ATTA method yields substantial performance improvements over TTA methods while maintaining efficiency and shares similar effectiveness to the more demanding active domain adaptation (ADA) methods. Our code is available at https://github.com/divelab/ATTA

Masatoshi Uehara, Xingyu Su, Yulai Zhao et al. · princeton

To fully leverage the capabilities of diffusion models, we are often interested in optimizing downstream reward functions during inference. While numerous algorithms for reward-guided generation have been recently proposed due to their significance, current approaches predominantly focus on single-shot generation, transitioning from fully noised to denoised states. We propose a novel framework for inference-time reward optimization with diffusion models inspired by evolutionary algorithms. Our approach employs an iterative refinement process consisting of two steps in each iteration: noising and reward-guided denoising. This sequential refinement allows for the gradual correction of errors introduced during reward optimization. Besides, we provide a theoretical guarantee for our framework. Finally, we demonstrate its superior empirical performance in protein and cell-type-specific regulatory DNA design. The code is available at \href{https://github.com/masa-ue/ProDifEvo-Refinement}{https://github.com/masa-ue/ProDifEvo-Refinement}.

Shurui Gui, Deep Anil Patel, Xiner Li et al.

Recent advances in video diffusion models have enabled the generation of high-quality videos. However, these videos still suffer from unrealistic deformations, semantic violations, and physical inconsistencies that are largely rooted in the absence of 3D physical priors. To address these challenges, we propose an object-aware 4D human motion generation framework grounded in 3D Gaussian representations and motion diffusion priors. With pre-generated 3D humans and objects, our method, Motion Score Distilled Interaction (MSDI), employs the spatial and prompt semantic information in large language models (LLMs) and motion priors through the proposed Motion Diffusion Score Distillation Sampling (MSDS). The combination of MSDS and LLMs enables our spatial-aware motion optimization, which distills score gradients from pre-trained motion diffusion models, to refine human motion while respecting object and semantic constraints. Unlike prior methods requiring joint training on limited interaction datasets, our zero-shot approach avoids retraining and generalizes to out-of-distribution object aware human motions. Experiments demonstrate that our framework produces natural and physically plausible human motions that respect 3D spatial context, offering a scalable solution for realistic 4D generation.

Edward De Brouwer, Carl Edwards, Alexander Wu et al.

Recent advances in machine learning and large-scale biological data collections have revived the prospect of building a virtual cell, a computational model of cellular behavior that could accelerate biological discovery. One of the most compelling promises of this vision is the ability to perform in silico phenotypic screens, in which a model predicts the effects of cellular perturbations in unseen biological contexts. This task combines heterogeneous textual inputs with diverse phenotypic outputs, making it particularly well-suited to LLMs and agentic systems. Yet, no standard benchmark currently exists for this task, as existing efforts focus on narrower molecular readouts that are only indirectly aligned with the phenotypic endpoints driving many real-world drug discovery workflows. In this work, we present AssayBench, a benchmark for phenotypic screen prediction, built from 1,920 publicly available CRISPR screens spanning five broad classes of cellular phenotypes. We formulate the screen prediction task as a gene rank prediction for each screen and introduce the adjusted nDCG, a continuous metric for comparing performance across heterogeneous assays. Our extensive evaluation shows that existing methods remain far from empirically estimated performance ceilings and zero-shot generalist LLMs outperform biology-specific LLMs and trainable baselines. Optimization techniques such as fine-tuning, ensembling, and prompt optimization can further improve LLM performance on this task. Overall, AssayBench offers a practical testbed for measuring progress toward in silico phenotypic screening and, more broadly, virtual cell models.

Xingyu Su, Xiner Li, Yuchao Lin et al.

We consider controllable DNA sequence design, where sequences are generated by conditioning on specific biological properties. While language models (LMs) such as GPT and BERT have achieved remarkable success in natural language generation, their application to DNA sequence generation remains largely underexplored. In this work, we introduce ATGC-Gen, an Automated Transformer Generator for Controllable Generation, which leverages cross-modal encoding to integrate diverse biological signals. ATGC-Gen is instantiated with both decoder-only and encoder-only transformer architectures, allowing flexible training and generation under either autoregressive or masked recovery objectives. We evaluate ATGC-Gen on representative tasks including promoter and enhancer sequence design, and further introduce a new dataset based on ChIP-Seq experiments for modeling protein binding specificity. Our experiments demonstrate that ATGC-Gen can generate fluent, diverse, and biologically relevant sequences aligned with the desired properties. Compared to prior methods, our model achieves notable improvements in controllability and functional relevance, highlighting the potential of language models in advancing programmable genomic design. The source code is released at (https://github.com/divelab/AIRS/blob/main/OpenBio/ATGC_Gen).

Shurui Gui, Xiner Li, Shuiwang Ji

We consider learning underlying laws of dynamical systems governed by ordinary differential equations (ODE). A key challenge is how to discover intrinsic dynamics across multiple environments while circumventing environment-specific mechanisms. Unlike prior work, we tackle more complex environments where changes extend beyond function coefficients to entirely different function forms. For example, we demonstrate the discovery of ideal pendulum's natural motion $α^2 \sin{θ_t}$ by observing pendulum dynamics in different environments, such as the damped environment $α^2 \sin(θ_t) - ρω_t$ and powered environment $α^2 \sin(θ_t) + ρ\frac{ω_t}{\left|ω_t\right|}$. Here, we formulate this problem as an \emph{invariant function learning} task and propose a new method, known as \textbf{D}isentanglement of \textbf{I}nvariant \textbf{F}unctions (DIF), that is grounded in causal analysis. We propose a causal graph and design an encoder-decoder hypernetwork that explicitly disentangles invariant functions from environment-specific dynamics. The discovery of invariant functions is guaranteed by our information-based principle that enforces the independence between extracted invariant functions and environments. Quantitative comparisons with meta-learning and invariant learning baselines on three ODE systems demonstrate the effectiveness and efficiency of our method. Furthermore, symbolic regression explanation results highlight the ability of our framework to uncover intrinsic laws. Our code has been released as part of the AIRS library (\href{https://github.com/divelab/AIRS/tree/main/OpenODE/DIF}{https://github.com/divelab/AIRS/}).

Xiner Li, Masatoshi Uehara, Xingyu Su et al.

Diffusion models have shown promising generative capabilities across diverse domains, yet aligning their outputs with desired reward functions remains a challenge, particularly in cases where reward functions are non-differentiable. Some gradient-free guidance methods have been developed, but they often struggle to achieve optimal inference-time alignment. In this work, we newly frame inference-time alignment in diffusion as a search problem and propose Dynamic Search for Diffusion (DSearch), which subsamples from denoising processes and approximates intermediate node rewards. It also dynamically adjusts beam width and tree expansion to efficiently explore high-reward generations. To refine intermediate decisions, DSearch incorporates adaptive scheduling based on noise levels and a lookahead heuristic function. We validate DSearch across multiple domains, including biological sequence design, molecular optimization, and image generation, demonstrating superior reward optimization compared to existing approaches.

Keqiang Yan, Xiner Li, Hongyi Ling et al.

We consider the problem of crystal materials generation using language models (LMs). A key step is to convert 3D crystal structures into 1D sequences to be processed by LMs. Prior studies used the crystallographic information framework (CIF) file stream, which fails to ensure SE(3) and periodic invariance and may not lead to unique sequence representations for a given crystal structure. Here, we propose a novel method, known as Mat2Seq, to tackle this challenge. Mat2Seq converts 3D crystal structures into 1D sequences and ensures that different mathematical descriptions of the same crystal are represented in a single unique sequence, thereby provably achieving SE(3) and periodic invariance. Experimental results show that, with language models, Mat2Seq achieves promising performance in crystal structure generation as compared with prior methods.

Xingyu Su, Xiner Li, Masatoshi Uehara et al. · princeton

We address the problem of fine-tuning diffusion models for reward-guided generation in biomolecular design. While diffusion models have proven highly effective in modeling complex, high-dimensional data distributions, real-world applications often demand more than high-fidelity generation, requiring optimization with respect to potentially non-differentiable reward functions such as physics-based simulation or rewards based on scientific knowledge. Although RL methods have been explored to fine-tune diffusion models for such objectives, they often suffer from instability, low sample efficiency, and mode collapse due to their on-policy nature. In this work, we propose an iterative distillation-based fine-tuning framework that enables diffusion models to optimize for arbitrary reward functions. Our method casts the problem as policy distillation: it collects off-policy data during the roll-in phase, simulates reward-based soft-optimal policies during roll-out, and updates the model by minimizing the KL divergence between the simulated soft-optimal policy and the current model policy. Our off-policy formulation, combined with KL divergence minimization, enhances training stability and sample efficiency compared to existing RL-based methods. Empirical results demonstrate the effectiveness and superior reward optimization of our approach across diverse tasks in protein, small molecule, and regulatory DNA design.

Lianhao Zhou, Hongyi Ling, Cong Fu et al.

Computing has long served as a cornerstone of scientific discovery. Recently, a paradigm shift has emerged with the rise of large language models (LLMs), introducing autonomous systems, referred to as agents, that accelerate discovery across varying levels of autonomy. These language agents provide a flexible and versatile framework that orchestrates interactions with human scientists, natural language, computer language and code, and physics. This paper presents our view and vision of LLM-based scientific agents and their growing role in transforming the scientific discovery lifecycle, from hypothesis discovery, experimental design and execution, to result analysis and refinement. We critically examine current methodologies, emphasizing key innovations, practical achievements, and outstanding limitations. Additionally, we identify open research challenges and outline promising directions for building more robust, generalizable, and adaptive scientific agents. Our analysis highlights the transformative potential of autonomous agents to accelerate scientific discovery across diverse domains.

Chi-Min Chan, Ehsan Hajiramezanali, Xiner Li et al.

In scientific reasoning tasks, the veracity of the reasoning process is as critical as the final outcome. While Process Reward Models (PRMs) offer a solution to the coarse-grained supervision problems inherent in Outcome Reward Models (ORMs), their deployment is hindered by the prohibitive cost of obtaining expert-verified step-wise labels. This paper addresses the challenge of training reliable PRMs using abundant but noisy "weak" supervision. We argue that existing Weak-to-Strong Generalization (W2SG) theories lack prescriptive guidelines for selecting high-quality training signals from noisy data. To bridge this gap, we introduce the Dual-Consensus Weak-to-Strong (DC-W2S) framework. By intersecting Self-Consensus (SC) metrics among weak supervisors with Neighborhood-Consensus (NC) metrics in the embedding space, we stratify supervision signals into distinct reliability regimes. We then employ a curriculum of instance-level balanced sampling and label-level reliability-aware masking to guide the training process. We demonstrate that DC-W2S enables the training of robust PRMs for complex reasoning without exhaustive expert annotation, proving that strategic data curation is more effective than indiscriminate training on large-scale noisy datasets.

Sambhav Khurana, Xiner Li, Shurui Gui et al.

Large language models (LLMs) are being increasingly explored for graph tasks. Despite their remarkable success in text-based tasks, LLMs' capabilities in understanding explicit graph structures remain limited, particularly with large graphs. In this work, we introduce Hierarchical Language Model for Graph (HLM-G), which employs a two-block architecture to capture node-centric local information and interaction-centric global structure, effectively enhancing graph structure understanding abilities. The proposed scheme allows LLMs to address various graph queries with high efficacy, efficiency, and robustness, while reducing computational costs on large-scale graph tasks. Furthermore, we demonstrate the interpretability of our model using intrinsic attention weights and established explainers. Comprehensive evaluations across diverse graph reasoning and real-world tasks of node, link, and graph-levels highlight the superiority of our method, marking a significant advancement in the application of LLMs to graph understanding.