Crossmodal matching in single-cell omics is essential for explaining biological regulatory mechanisms and enhancing downstream analyses. However, current single-cell crossmodal models often suffer from three limitations: sparse modality signals, underutilization of biological attributes, and insufficient modeling of regulatory interactions. These challenges hinder generalization in data-scarce settings and restrict the ability to uncover fine-grained biologically meaningful crossmodal relationships. Here, we present a novel framework which reformulates crossmodal matching as a graph classification task on Attributed Bipartite Graphs (ABGs). It models single-cell ATAC-RNA data as an ABG, where each expressed ATAC and RNA is treated as a distinct node with unique IDs and biological features. To model crossmodal interaction patterns on the constructed ABG, we propose Bi2Former, a biologically-driven bipartite graph transformer that learns interpretable attention over ATAC-RNA pairs. This design enables the model to effectively learn and explain biological regulatory relationships between ATAC and RNA modalities. Extensive experiments demonstrate that Bi2Former achieves state-of-the-art performance in crossmodal matching across diverse datasets, remains robust under sparse training data, generalizes to unseen cell types and datasets, and reveals biologically meaningful regulatory patterns.

Deep neural networks trained to predict neural activity from visual input and behaviour have shown great potential to serve as digital twins of the visual cortex. Per-neuron embeddings derived from these models could potentially be used to map the functional landscape or identify cell types. However, state-of-the-art predictive models of mouse V1 do not generate functional embeddings that exhibit clear clustering patterns which would correspond to cell types. This raises the question whether the lack of clustered structure is due to limitations of current models or a true feature of the functional organization of mouse V1. In this work, we introduce DECEMber - Deep Embedding Clustering via Expectation Maximization-based refinement - an explicit inductive bias into predictive models that enhances clustering by adding an auxiliary t-distribution-inspired loss function that enforces structured organization among per-neuron embeddings.

How precisely does circuit wiring specify function? This fundamental question is particularly relevant for modern neuroscience, as large-scale electron microscopy now enables the reconstruction of neural circuits at single-synapse resolution across many organisms. To interpret circuit function from such datasets, we must understand the extent to which the measured structure constrains dynamics. We investigate this question in the Drosophila head direction (HD) circuit, which maintains an internal heading estimate through attractor dynamics that integrate self-motion velocity cues. This circuit serves as a sensitive assay for functional specification: continuous attractor networks are theoretically known to require finely tuned wiring symmetries, whereas connectomes omit key cellular parameters such as synaptic gains, neuronal thresholds, and time constants, and reveal that biological wiring can be heterogeneous. We introduce a method that combines selfsupervised and unsupervised learning objectives to estimate unknown parameters at the level of cell types, rather than individual neurons and synapses. Starting from the raw connectivity matrix, our approach recovers a network that exhibits continuous attractor dynamics and accurately integrates a range of velocity inputs, despite minimal parameter tuning on a connectome that notably departs from the symmetric regularity of an idealized ring attractor. We characterize how deviations from the original connectome shape the space of viable solutions. We also perform in-silico ablation experiments to probe the distinct functional roles of specific cell types in the circuit, demonstrating how connectome-derived structure, when augmented with minimal, biologically grounded tuning, can replicate known physiology and elucidate circuit function.

Neurons process information in ways that depend on their cell type, connectivity, and the brain region in which they are embedded. However, inferring these factors from neural activity remains a significant challenge. To build general-purpose representations that allow for resolving information about a neuron's identity, we introduce NuCLR, a self-supervised framework that aims to learn representations of neural activity that allow for differentiating one neuron from the rest. NuCLRbrings together views of the same neuron observed at different times and across different stimuli and uses a contrastive objective to pull these representations together. To capture population context without assuming any fixed neuron ordering, we build a spatiotemporal transformer that integrates activity in a permutation-equivariant manner.

Recent studies have demonstrated the feasibility of modeling single-cell data as natural languages and the potential of leveraging powerful large language models (LLMs) for understanding cell biology. However, a comprehensive evaluation of LLMs' performance on language-driven single-cell analysis tasks remains unexplored. Motivated by this challenge, we introduce CELLVERSE, a unified language-centric question-answering benchmark that integrates four types of single-cell multi-omics data and encompasses three hierarchical levels of single-cell analysis tasks: cell type annotation (cell-level), drug response prediction (drug-level), and perturbation analysis (gene-level). Going beyond this, we systematically evaluate the performance across 14 open-source and closed-source LLMs ranging 160M 671B on CELLVERSE. Remarkably, the experimental results reveal: Existing specialist models (e.g., C2S-Pythia) fail to make reasonable decisions across all sub-tasks within CELLVERSE, while generalist models such as Qwen, Llama, GPT, and DeepSeekfamily models exhibit preliminary understanding capabilities within the realm of cell biology. The performance of current LLMs falls short of expectations and has substantial room for improvement. Notably, in the widely studied drug response prediction task, none of the evaluated LLMs demonstrate significant performance improvement over random guessing. CELLVERSE offers the first large-scale empirical demonstration that significant challenges still remain in applying LLMs to cell biology. By introducing CELLVERSE, we lay the foundation for advancing cell biology through natural languages and hope this paradigm could facilitate next-generation single-cell analysis.

Spatial transcriptomics technologies can be used to align transcriptomes with histopathological morphology, presenting exciting new opportunities for biomolecular discovery. Using spatial transcriptomic gene expression and corresponding histology data, we construct a novel framework, GeneFlow, to map single-and multi-cell gene expression onto paired cellular images. By combining an attentionbased RNA encoder with a conditional UNet guided by rectified flow, we generate high-resolution images with different staining methods (e.g., H&E, DAPI) to highlight various cellular/ tissue structures. Rectified flow with high-order ODE solvers creates a continuous, bijective mapping between expression and image manifolds, addressing the many-to-one relationship inherent in this problem. Our method enables the generation of realistic cellular morphology features and spatially resolved intercellular interactions under genetic or chemical perturbations. This enables minimally invasive disease diagnosis by revealing dysregulated patterns in imaging phenotypes. Our rectified flow based method outperforms diffusion methods and baselines in all experiments.

In neuroscience, models that learn representations of single-neuron in-vivo activity are essential for understanding the functional identities of individual neurons. The primary goal of these models--spanning Transformer-based, contrastive, and variational autoencoder frameworks, is not to predict neural activity, but to distill it into a stable, low-dimensional embedding that captures a neuron's intrinsic features. These learned identity embeddings should be invariant to changing experimental conditions while reflecting the neuron's molecular type and anatomical location, thus enabling downstream tasks like in-vivo cell type prediction. However, current models suffer from limited generalizability due to batch effects: non-biological variations arising from differences in experimental design, animal subjects, or recording platforms. These batch effects cause overfitting, reducing model robustness and utility.

Designing regulatory DNA sequences that achieve precise cell-type-specific gene expression is crucial for advancements in synthetic biology, gene therapy and precision medicine. Although transformer-based language models (LMs) can effectively capture patterns in regulatory DNA, their generative approaches often struggle to produce novel sequences with reliable cell-type-specific activity. Here, we introduce Ctrl-DNA, a novel constrained reinforcement learning (RL) framework tailored for designing regulatory DNA sequences with controllable cell-type specificity. By formulating regulatory sequence design as a biologically informed constrained optimization problem, we apply RL to autoregressive genomic LMs, enabling the models to iteratively refine sequences that maximize regulatory activity in targeted cell types while constraining off-target effects. Our evaluation on human promoters and enhancers demonstrates that Ctrl-DNA consistently outperforms existing generative and RL-based approaches, generating high-fitness regulatory sequences and achieving state-of-the-art cell-type specificity. Moreover, Ctrl-DNA-generated sequences capture key cell-type-specific transcription factor binding sites (TFBS), short DNA motifs recognized by regulatory proteins that control gene expression, demonstrating the biological plausibility of the generated sequences.

Clustering is widely used for exploratory analysis and scientific discovery, driving insights from market segmentation to biological data analysis, but its outputs can be difficult to interpret, audit, and reproduce as modern datasets become increasingly large and complex. Reliable use of clustering requires understanding which features drive the discovered structure, yet feature-level explanations for clustering remain scarce compared with methods in supervised learning. Furthermore, existing clustering feature importance scores are often tied to specific algorithms and data assumptions. To address these challenges, we propose Cluster LOCO (Leave-One-Covariate-Out), a family of model-agnostic feature importance scores for clustering. Cluster LOCO is built on feature occlusion and clustering generalizability, defined as whether cluster labels learned on one subset of the data can be accurately predicted on held-out samples. For any chosen clustering algorithm, Cluster LOCO quantifies a feature's importance by measuring how much its removal degrades generalizability. We first introduce Cluster LOCO-Split, which relies on data splitting, and then extend it to Cluster LOCO-MP, a minipatch ensemble-based version designed for large-scale data. Across synthetic simulations and an application to cell-type discovery in single-cell transcriptomics, we show that Cluster LOCO more reliably recovers informative features than existing clustering feature importance methods.

Deep neural networks trained to predict neural activity from visual input and behaviour have shown great potential to serve as digital twins of the visual cortex. Per-neuron embeddings derived from these models could potentially be used to map the functional landscape or identify cell types. However, state-of-the-art predictive models of mouse V1 do not generate functional embeddings that exhibit clear clustering patterns which would correspond to cell types. This raises the question whether the lack of clustered structure is due to limitations of current models or a true feature of the functional organization of mouse V1. In this work, we introduce DECEMber -- Deep Embedding Clustering via Expectation Maximization-based refinement -- an explicit inductive bias into predictive models that enhances clustering by adding an auxiliary $t$-distribution-inspired loss function that enforces structured organization among per-neuron embeddings.