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Applications · Chemistry, Physics, and Earth Sciences

Zhang Jiasheng, Delvin Zhang, Shuang Liang, Zhengpin Li, ZHITAO YING, Jie Shao

Protein language models often struggle to capture biological functions due to their lack of factual knowledge (e.g., gene descriptions). Existing solutions leverage protein knowledge graphs (PKGs) as auxiliary pre-training objectives, but lack explicit integration of task-oriented knowledge, making them suffer from limited knowledge exploitation and catastrophic forgetting. The root cause is that they fail to align PKGs with task-specific data, forcing their knowledge modeling to adapt to the knowledge-isolated nature of downstream tasks. In this paper, we propose Knowledge-aware retrieval augmented protein language model (Kara), achieving the first task-oriented and explicit integration of PKGs and protein language models. With a knowledge retriever learning to predict linkages between PKG and task proteins, Kara unifies the knowledge integration of the pre-training and fine-tuning stages with a structure-based regularization, mitigating catastrophic forgetting. To ensure task-oriented integration, Kara uses contextualized virtual tokens to extract graph context as task-specific knowledge for new proteins. Experiments show that Kara outperforms existing knowledge-enhanced models in 6 representative tasks, achieving on average 5.1% improvements.

General Machine Learning · Representation Learning

Yuanchao Xu, Kaidi Shao, Nikos Logothetis, Zhongwei Shen

Analyzing the long-term behavior of high-dimensional nonlinear dynamical systems remains a significant challenge. While the Koopman operator framework provides a powerful global linearization tool, current methods for approximating its spectral components often face theoretical limitations and depend on predefined dictionaries. Residual Dynamic Mode Decomposition (ResDMD) advanced the field by introducing the \emph{spectral residual} to assess Koopman operator approximation accuracy; however, its approach of only filtering precomputed spectra prevents the discovery of the operator's complete spectral information, a limitation known as the `spectral inclusion' problem. We introduce ResKoopNet (Residual-based Koopman-learning Network), a novel method that directly addresses this by explicitly minimizing the \emph{spectral residual} to compute Koopman eigenpairs. This enables the identification of a more precise and complete Koopman operator spectrum. Using neural networks, our approach provides theoretical guarantees while maintaining computational adaptability. Experiments on a variety of physical and biological systems show that ResKoopNet achieves more accurate spectral approximations than existing methods, particularly for high-dimensional systems and those with continuous spectra, which demonstrates its effectiveness as a tool for analyzing complex dynamical systems.

Deep Learning · Graph Neural Networks

Gregoire Fournier, Sourav Medya

Graph neural networks (GNNs) have been widely used in various domains such as social networks, molecular biology, or recommendation systems. Concurrently, different explanations methods of GNNs have arisen to complement its blackbox nature. Explanations of the GNNs’ predictions can be categorized into two types—factual and counterfactual. Given a GNN trained on binary classification into “accept” and “reject” classes, a global counterfactual explanation consists in generating a small set of “accept” graphs relevant to all of the input “reject” graphs. The transformation of a “reject” graph into an “accept” graph is called a recourse. A common recourse explanation is a small set of recourse, from which every “reject” graph can be turned into an “accept” graph. Although local counterfactual explanations have been studied extensively, the problem of finding common recourse for global counterfactual explanation remains unexplored, particularly for GNNs. In this paper, we formalize the common recourse explanation problem, and design an effective algorithm, COMRECGC, to solve it. We benchmark our algorithm against strong baselines on four different real-world graphs datasets and demonstrate the superior performance of COMRECGC against the competitors. We also compare the common recourse explanations to the graph counterfactual explanation, showing that common recourse explanations are either comparable or superior, making them worth considering for applications such as drug discovery or computational biology.

Theory · Domain Adaptation and Transfer Learning

Akhil Jalan, Yassir Jedra, Arya Mazumdar, Soumendu Sundar Mukherjee, Purnamrita Sarkar

We study transfer learning for matrix completion in a Missing Not-at-Random (MNAR) setting that is motivated by biological problems. The target matrix $Q$ has entire rows and columns missing, making estimation impossible without side information. To address this, we usea noisy and incomplete source matrix $P$, which relates to $Q$ via a feature shift in latent space. We consider both the *active* and *passive* sampling of rows and columns. We establish minimax lower bounds for entrywise estimation error in each setting. Our computationally efficient estimation framework achieves this lower bound for the active setting, which leverages the source data to query the most informative rows and columns of $Q$. This avoids the need for *incoherence* assumptions required for rate optimality in the passive sampling setting. We demonstrate the effectiveness of our approach through comparisons with existing algorithms on real-world biological datasets.

Applications · Health / Medicine

Da Kuang, GuanWen Qiu, Junhyong Kim

How a single fertilized cell gives rise to a complex array of specialized cell types in development is a central question in biology. The cells replicate to generate cell lineages and acquire differentiated characteristics through poorly understood molecular processes. A key approach to studying developmental processes is to infer the tree graph of cell lineage histories, which provides an analytical framework for dissecting individual cells' molecular decisions during replication and differentiation (i.e., acquisition of specialized traits). Although genetically engineered lineage-tracing methods have advanced the field, they are either infeasible or ethically constrained in many organisms. By contrast, modern single-cell technologies can measure high-content molecular profiles (*e.g.*, transcriptomes) in a wide range of biological systems. Here, we introduce *CellTreeQM*, a novel deep learning method based on transformer architectures that learns an embedding space with geometric properties optimized for tree-graph inference. By formulating the lineage reconstruction problem as tree-metric learning, we systematically explore weakly supervised training settings at different levels of information and present the *Cell Lineage Reconstruction Benchmark* to facilitate comprehensive evaluation. This benchmark includes (1) synthetic data modeled via Brownian motion with independent noise and spurious signals; (2) lineage-resolved single-cell RNA sequencing datasets. Experimental results show that *CellTreeQM* recovers lineage structures with minimal supervision and limited data, offering a scalable framework for uncovering cell lineage relationships. To our knowledge, this is the first method to cast cell lineage inference explicitly as a metric learning task, paving the way for future computational models aimed at uncovering the molecular dynamics of cell lineage. Code and benchmarks are available at: https://kuang-da.github.io/CellTreeQM-page

Deep Learning · Sequential Models, Time series

Wenjie Wu, Dexuan Huo, Hong Chen

Spiking Neural Networks (SNNs) have demonstrated remarkable potential across many domains, including computer vision and natural language processing, owing to their energy efficiency and biological plausibility. However, their application in long-term prediction tasks remains underexplored, which is primarily due to two critical challenges: (1) current SNN encoding methods are unable to effectively encode long temporal information, leading to increased computational complexity and energy consumption; (2) though Transformer-based models have achieved state-of-the-art accuracy in temporal prediction tasks, the absence of proper positional encoding for spiking self-attention restricts Spiking Transformer from effectively utilizing positional information, resulting in performance degradation. To address these challenges, we introduce an attention-free framework, **Spik**ing **F**ourier Network (**SpikF**), that encodes input sequences in patches and employs an innovative frequency domain selection mechanism to effectively utilize the sequential properties of time-series data. Extensive evaluations on eight well-established long-term prediction datasets demonstrate that SpikF achieves an averaged $1.9\\%$ reduction in Mean Absolute Error (MAE) compared to state-of-the-art models, while lowering total energy consumption by $3.16\times$. Our code is available at https://github.com/WWJ-creator/SpikF.

Applications · Health / Medicine

Hongru Hu, Shuwen Zhang, Yongin Choi, Venkat Malladi, Gerald Quon

Single-cell RNA sequencing (scRNA-seq) enables high-resolution exploration of cellular diversity and gene regulation, yet analyzing such data remains challenging due to technical and methodological limitations. Existing task-specific deep generative models like Variational Auto-Encoder (VAE) and its variants struggle to incorporate external biological knowledge, while transformer-based foundational large Language Models (LLMs or large LaMs) face limitations in computational cost and applicability to tabular gene expression data. Here, we introduce sciLaMA (single-cell interpretable Language Model Adapter), a novel representation learning framework that bridges these gaps by integrating static gene embeddings from multimodal LaMs with scRNA-seq tabular data through a paired-VAE architecture. Our approach generates context-aware representations for both cells and genes and outperforms state-of-the-art methods in key single-cell downstream tasks, including batch effect correction, cell clustering, and cell-state-specific gene marker and module identification, while maintaining computational efficiency. sciLaMA offers a computationally efficient, unified framework for comprehensive single-cell data analysis and biologically interpretable gene module discovery.

General Machine Learning · Transfer, Multitask and Meta-learning

Gaole Dai, Chun-Kai Fan, Yiming Tang, Zhi Zhang, Yuan Zhang, Yulu Gan, Qizhe Zhang, Cheng-Ching Tseng, Shanghang Zhang, Tiejun Huang

Advances in Parameter-efficient Fine-tuning (PEFT) bridged the performance gap with Full Fine-Tuning (FFT) through sophisticated analysis of pre-trained parameter spaces. Starting from drawing insights from Neural Engrams (NE) in Biological Neural Networks (BNNs), we establish a connection between the low-rank property observed during PEFT's parameter space shifting and neurobiological mechanisms. This observation leads to our proposed method, **S**ynapse and **N**euron (**SAN**), which decomposes and propagates the scaling component from anterior feature adjustment vectors towards posterior weight matrices. Our approach is theoretically grounded in Long-Term Potentiation/Depression (LTP/D) phenomena, which govern synapse development through neurotransmitter release modulation. Extensive experiments demonstrate its effectiveness: on **vision tasks** across VTAB, FGVC, and GIC (25 datasets) using ViT, Swin-T and ConvNeXt architectures, SAN outperforms FFT up to *8.7%* and LoRA by *3.2%*; on **language tasks** using Commonsense Reasoning (8 datasets) with LLaMA models (all generations), surpassing ChatGPT up to *8.5%* and LoRA by *4.7%*; on **vision-language tasks** using Visual Instruction Tuning (7 datasets) with LLaVA models, it exceeds FFT up to *2.4%* and LoRA by *1.9%*. Our code and W&B log will be released

Applications · Health / Medicine

Arthur Deng, Karsten Householder, Fang Wu, K. Garcia, Brian Trippe

Accurate estimation of mutational effects on protein-protein binding energies is an open problem with applications in structural biology and therapeutic design. Several deep learning predictors for this task have been proposed but, presumably due to the scarcity of binding data, these methods under-perform computationally expensive estimates based on empirical force-fields. In response, we propose a transfer-learning approach that leverages advances in protein sequence modeling and folding stability prediction for this task. The key idea is to parameterize the binding energy as the difference between the folding energy of the protein complex and the sum of the folding energies of its binding partners. We show that using a pre-trained inverse-folding model as a proxy for folding energy provides strong zero-shot performance, and can be fine-tuned with (1) copious folding energy measurements and (2) more limited binding energy measurements.The resulting predictor, StaB-ddG, is the first deep learning predictor to match the accuracy of the state-of-the-art empirical force-field method Flex ddG, while offering an over 10,000x speed-up.

General Machine Learning · Hardware and Software

Chuan Liu, Chunshu Wu, Ruibing Song, Ang Li, Ying Nian Wu, Tong Geng

Function learning forms the foundation of numerous scientific and engineering tasks. While modern machine learning (ML) methods model complex functions effectively, their escalating complexity and computational demands pose challenges to efficient deployment. In contrast, natural dynamical systems exhibit remarkable computational efficiency in representing and solving complex functions. However, existing dynamical system approaches are limited by low expressivity and inefficient training. To this end, we propose EADS, an Expressive and self-Adaptive Dynamical System capable of accurately learning a wide spectrum of functions with extraordinary efficiency. Specifically, (1) drawing inspiration from biological dynamical systems, we integrate hierarchical architectures and heterogeneous dynamics into EADS, significantly enhancing its capacity to represent complex functions. (2) We propose an efficient on-device training method that leverages intrinsic electrical signals to update parameters, making EADS self-adaptive at negligible cost. Experimental results across diverse domains demonstrate that EADS achieves higher accuracy than existing works, while offering orders-of-magnitude speedups and energy efficiency over traditional neural network solutions on GPUs for both inference and training, showcasing its broader impact in overcoming computational bottlenecks across various fields.

Applications · Computer Vision

Velibor Bojkovic, Xiaofeng Wu, Bin Gu

Spiking Neural Networks (SNNs) offer a more energy-efficient alternative to Artificial Neural Networks (ANNs) by mimicking biological neural principles, establishing them as a promising approach to mitigate the increasing energy demands of large-scale neural models. However, fully harnessing the capabilities of SNNs remains challenging due to their discrete signal processing and temporal dynamics. ANN-SNN conversion has emerged as a practical approach, enabling SNNs to achieve competitive performance on complex machine learning tasks. In this work, we identify a phenomenon in the ANN-SNN conversion framework, termed *temporal misalignment*, in which random spike rearrangement across SNN layers leads to performance improvements. Based on this observation, we introduce biologically plausible two-phase probabilistic (TPP) spiking neurons, further enhancing the conversion process. We demonstrate the advantages of our proposed method both theoretically and empirically through comprehensive experiments on CIFAR-10/100, CIFAR10-DVS, and ImageNet across a variety of architectures, achieving state-of-the-art results.

Applications · Computer Vision

Zechen Bai, Hai Ci, Mike Zheng Shou

Synthetic videos nowadays is widely used to complement data scarcity and diversity of real-world videos.Current synthetic datasets primarily replicate real-world scenarios, leaving impossible, counterfactual and anti-reality video concepts underexplored. This work aims to answer two questions: 1) Can today's video generation models effectively follow prompts to create impossible video content? 2) Are today's video understanding models good enough for understanding impossible videos?To this end, we introduce *IPV-Bench*, a novel benchmark designed to evaluate and foster progress in video understanding and generation. *IPV-Bench* is underpinned by a comprehensive taxonomy, encompassing 4 domains, 14 categories.It features diverse scenes that defy physical, biological, geographical, or social laws. Based on the taxonomy, a prompt suite is constructed to evaluate video generation models, challenging their prompt following and creativity capabilities. In addition, a video benchmark is curated to assess Video-LLMs on their ability of understanding impossible videos, which particularly requires reasoning on temporal dynamics and world knowledge. Comprehensive evaluations reveal limitations and insights for future directions of video models, paving the way for next-generation video models.

Applications · Health / Medicine

Suyuan Zhao, YIZHEN LUO, Ganbo Yang, Yan Zhong, Hao Zhou, Zaiqing Nie

Spatial Transcriptomics (ST) technologies provide biologists with rich insights into single-cell biology by preserving spatial context of cells.Building foundational models for ST can significantly enhance the analysis of vast and complex data sources, unlocking new perspectives on the intricacies of biological tissues. However, modeling ST data is inherently challenging due to the need to extract multi-scale information from tissue slices containing vast numbers of cells. This process requires integrating macro-scale tissue morphology, micro-scale cellular microenvironment, and gene-scale gene expression profile.To address this challenge, we propose **SToFM**, a multi-scale **S**patial **T**ranscript**o**mics **F**oundation **M**odel.SToFM first performs multi-scale information extraction on each ST slice, to construct a set of ST sub-slices that aggregate macro-, micro- and gene-scale information. Then an SE(2) Transformer is used to obtain high-quality cell representations from the sub-slices.Additionally, we construct **SToCorpus-88M**, the largest high-resolution spatial transcriptomics corpus for pretraining. SToFM achieves outstanding performance on a variety of downstream tasks, such as tissue region semantic segmentation and cell type annotation, demonstrating its comprehensive understanding of ST data through capturing and integrating multi-scale information.

Applications · Chemistry, Physics, and Earth Sciences

Pengkang Guo, Bruno Correia, Pierre Vandergheynst, Daniel Probst

Machine learning for protein modeling faces significant challenges due to proteins' inherently dynamic nature, yet most graph-based machine learning methods rely solely on static structural information. Recently, the growing availability of molecular dynamics trajectories provides new opportunities for understanding the dynamic behavior of proteins; however, computational methods for utilizing this dynamic information remain limited. We propose a novel graph representation that integrates both static structural information and dynamic correlations from molecular dynamics trajectories, enabling more comprehensive modeling of proteins. By applying relational graph neural networks (RGNNs) to process this heterogeneous representation, we demonstrate significant improvements over structure-based approaches across three distinct tasks: atomic adaptability prediction, binding site detection, and binding affinity prediction. Our results validate that combining static and dynamic information provides complementary signals for understanding protein-ligand interactions, offering new possibilities for drug design and structural biology applications.

Applications · Neuroscience, Cognitive Science

Pablo Samuel Castro, Nenad Tomasev, Ankit Anand, Navodita Sharma, Rishika Mohanta, Aparna Dev, Kuba Perlin, Siddhant Jain, Kyle Levin, Noemi Elteto 等

Symbolic models play a key role in cognitive science, expressing computationally precise hypotheses about how the brain implements a cognitive process. Identifying an appropriate model typically requires a great deal of effort and ingenuity on the part of a human scientist.Here, we adapt FunSearch (Romera-Paredes et al. 2024), a recently developed tool that uses Large Language Models (LLMs) in an evolutionary algorithm, to automatically discover symbolic cognitive models that accurately capture human and animal behavior.We consider datasets from three species performing a classic reward-learning task that has been the focus of substantial modeling effort, and find that the discovered programs outperform state-of-the-art cognitive models for each.The discovered programs can readily be interpreted as hypotheses about human and animal cognition, instantiating interpretable symbolic learning and decision-making algorithms. Broadly, these results demonstrate the viability of using LLM-powered program synthesis to propose novel scientific hypotheses regarding mechanisms of human and animal cognition.

Applications · Neuroscience, Cognitive Science

Kairong Yu, Tianqing Zhang, Qi Xu, Gang Pan, Hongwei Wang

Spiking Neural Networks (SNNs) are increasingly recognized for their biological plausibility and energy efficiency, positioning them as strong alternatives to Artificial Neural Networks (ANNs) in neuromorphic computing applications. SNNs inherently process temporal information by leveraging the precise timing of spikes, but balancing temporal feature utilization with low energy consumption remains a challenge. In this work, we introduce Temporal Shift module for Spiking Neural Networks (TS-SNN), which incorporates a novel Temporal Shift (TS) module to integrate past, present, and future spike features within a single timestep via a simple yet effective shift operation. A residual combination method prevents information loss by integrating shifted and original features. The TS module is lightweight, requiring only one additional learnable parameter, and can be seamlessly integrated into existing architectures with minimal additional computational cost. TS-SNN achieves state-of-the-art performance on benchmarks like CIFAR-10 (96.72\%), CIFAR-100 (80.28\%), and ImageNet (70.61\%) with fewer timesteps, while maintaining low energy consumption. This work marks a significant step forward in developing efficient and accurate SNN architectures.

Applications · Chemistry, Physics, and Earth Sciences

Koen Minartz, Tim d'Hondt, Leon Hillmann, Jörn Starruß, Lutz Brusch, Vlado Menkovski

The cellular Potts model (CPM) is a powerful computational method for simulating collective spatiotemporal dynamics of biological cells.To drive the dynamics, CPMs rely on physics-inspired Hamiltonians. However, as first principles remain elusive in biology, these Hamiltonians only approximate the full complexity of real multicellular systems.To address this limitation, we propose NeuralCPM, a more expressive cellular Potts model that can be trained directly on observational data.At the core of NeuralCPM lies the Neural Hamiltonian, a neural network architecture that respects universal symmetries in collective cellular dynamics.Moreover, this approach enables seamless integration of domain knowledge by combining known biological mechanisms and the expressive Neural Hamiltonian into a hybrid model.Our evaluation with synthetic and real-world multicellular systems demonstrates that NeuralCPM is able to model cellular dynamics that cannot be accounted for by traditional analytical Hamiltonians.

Applications · Neuroscience, Cognitive Science

Chi-Ning Chou, Hang Le, Yichen Wang, SueYeon Chung

Integrating task-relevant information into neural representations is a fundamental ability of both biological and artificial intelligence systems. Recent theories have categorized learning into two regimes: the rich regime, where neural networks actively learn task-relevant features, and the lazy regime, where networks behave like random feature models. Yet this simple lazy–rich dichotomy overlooks a diverse underlying taxonomy of feature learning, shaped by differences in learning algorithms, network architectures, and data properties. To address this gap, we introduce an analysis framework to study feature learning via the geometry of neural representations. Rather than inspecting individual learned features, we characterize how task-relevant representational manifolds evolve throughout the learning process. We show, in both theoretical and empirical settings, that as networks learn features, task-relevant manifolds untangle, with changes in manifold geometry revealing distinct learning stages and strategies beyond the lazy–rich dichotomy. This framework provides novel insights into feature learning across neuroscience and machine learning, shedding light on structural inductive biases in neural circuits and the mechanisms underlying out-of-distribution generalization.

Deep Learning · Large Language Models

Kexin Huang, Ying Jin, Ryan Li, Michael Li, Emmanuel J Candes, Jure Leskovec

Hypotheses are central to information acquisition, decision-making, and discovery. However, many real-world hypotheses are abstract, high-level statements that are difficult to validate directly. This challenge is further intensified by the rise of hypothesis generation from Large Language Models (LLMs), which are prone to hallucination and produce hypotheses in volumes that make manual validation impractical. Here we propose POPPER, an agentic framework for rigorous automated validation of free-form hypotheses. Guided by Karl Popper's principle of falsification, POPPER validates a hypothesis using LLM agents that design and execute falsification experiments targeting its measurable implications. A novel sequential testing framework ensures strict Type-I error control while actively gathering evidence from diverse observations, whether drawn from existing data or newly conducted procedures. We demonstrate POPPER on six domains including biology, economics, and sociology. POPPER delivers robust error control, high power, and scalability. Furthermore, compared to human scientists, POPPER achieved comparable performance in validating complex biological hypotheses while reducing time by 10 folds, providing a scalable, rigorous solution for hypothesis validation. POPPER is freely available at https://github.com/snap-stanford/POPPER.

Deep Learning · Graph Neural Networks

Artem Moskalev, Mangal Prakash, Junjie Xu, Tianyu Cui, Rui Liao, Tommaso Mansi

Processing global geometric context while preserving equivariance is crucial when modeling biological, chemical, and physical systems. Yet, this is challenging due to the computational demands of equivariance and global context at scale. Standard methods such as equivariant self-attention suffer from quadratic complexity, while local methods such as distance-based message passing sacrifice global information. Inspired by the recent success of state-space and long-convolutional models, we introduce Geometric Hyena, the first equivariant long-convolutional model for geometric systems. Geometric Hyena captures global geometric context at sub-quadratic complexity while maintaining equivariance to rotations and translations. Evaluated on all-atom property prediction of large RNA molecules and full protein molecular dynamics, Geometric Hyena outperforms existing equivariant models while requiring significantly less memory and compute that equivariant self-attention. Notably, our model processes the geometric context of $30k$ tokens $20 \times$ faster than the equivariant transformer and allows $72 \times$ longer context within the same budget.