Daily Papers

Recent advances have discussed cell complexes as ideal learning representations. However, there is a lack of available machine learning methods suitable for learning on CW complexes. In this paper, we derive an explicit expression for the Wasserstein distance between cell complex signal distributions in terms of a Hodge-Laplacian matrix. This leads to a structurally meaningful measure to compare CW complexes and define the optimal transportation map. In order to simultaneously include both feature and structure information, we extend the Fused Gromov-Wasserstein distance to CW complexes. Finally, we introduce novel kernels over the space of probability measures on CW complexes based on the dual formulation of optimal transport.

Latent Graph Inference (LGI) relaxed the reliance of Graph Neural Networks (GNNs) on a given graph topology by dynamically learning it. However, most of LGI methods assume to have a (noisy, incomplete, improvable, ...) input graph to rewire and can solely learn regular graph topologies. In the wake of the success of Topological Deep Learning (TDL), we study Latent Topology Inference (LTI) for learning higher-order cell complexes (with sparse and not regular topology) describing multi-way interactions between data points. To this aim, we introduce the Differentiable Cell Complex Module (DCM), a novel learnable function that computes cell probabilities in the complex to improve the downstream task. We show how to integrate DCM with cell complex message passing networks layers and train it in a end-to-end fashion, thanks to a two-step inference procedure that avoids an exhaustive search across all possible cells in the input, thus maintaining scalability. Our model is tested on several homophilic and heterophilic graph datasets and it is shown to outperform other state-of-the-art techniques, offering significant improvements especially in cases where an input graph is not provided.

Given a complex of groups G(Y) = (G_sigma, psi_a, g_{a,b}) where all G_sigma are relatively hyperbolic, the psi_a are inclusions of full relatively quasiconvex subgroups, and the universal cover X is CAT(0) and delta--hyperbolic, we show pi_1(G(Y)) is relatively hyperbolic. The proof extends the work of Dahmani and Martin by constructing a model for the Bowditch boundary of pi_1(G(Y)). We prove the model is a compact metrizable space on which G acts as a geometrically finite convergence group, and a theorem of Yaman then implies the result. More generally, this model shows how any suitable action of a relatively hyperbolic group on a simply connected cell complex encodes a decomposition of the Bowditch boundary into the boundary of the cell complex and the boundaries of cell stabilizers. We hope this decomposition will be helpful in answering topological questions about Bowditch boundaries.

We define a cell complex with an action of the even spin mapping class group, and use it to obtain a finite presentation. We also obtain a finite presentation with Dehn twist generators.

Actuator degradation turns quadruped locomotion into a coordination problem requiring joints to compensate for lost actuation. Prior work suggests that morphology-aware graph policies improve learning and generalization under body perturbations. We ask whether these benefits can be strengthened by explicitly modeling higher-order mechanical structure. We represent the Unitree Go1 as a cell complex with limb- and body-level rank-2 cells and apply Hodge-based message passing. Under degradation training, the node-edge-face Hodge actor achieves the highest return on unseen actuator degradations, with higher survival and lower velocity-tracking error. These results support higher-order morphology as a useful inductive bias for whole-body compensation under actuator degradation.

We introduce Topological Neural Operators (TNOs), a principled framework for operator learning on cell complexes that lifts neural operators (NOs) from functions on points and/or edges to topological domains. TNOs represent data as features defined on cells of varying dimension and model their interactions through Discrete Exterior Calculus, enabling explicit cross-dimensional coupling via gradient-, curl-, and divergence-type operators. The key design principle is to decouple where information flows, as governed by fixed topological operators, from how it is transformed (which is learned), yielding models that respect the geometric support of physical quantities and expose conservation and compatibility structure. We further propose Hierarchical TNOs (HTNOs), which incorporate learned coarse complexes to propagate long-range and topology-dependent information. Our framework subsumes existing NOs as a special case, providing a unified perspective on operator learning across discretizations. Across a range of PDE benchmarks, including irregular-geometry flow problems, TNOs and HTNOs improve accuracy; controlled studies further isolate the benefits of native higher-rank and topological structure. Project page: https://circle-group.github.io/research/TNO

This work introduces TopoBenchmarkX, a modular open-source library designed to standardize benchmarking and accelerate research in Topological Deep Learning (TDL). TopoBenchmarkX maps the TDL pipeline into a sequence of independent and modular components for data loading and processing, as well as model training, optimization, and evaluation. This modular organization provides flexibility for modifications and facilitates the adaptation and optimization of various TDL pipelines. A key feature of TopoBenchmarkX is that it allows for the transformation and lifting between topological domains. This enables, for example, to obtain richer data representations and more fine-grained analyses by mapping the topology and features of a graph to higher-order topological domains such as simplicial and cell complexes. The range of applicability of TopoBenchmarkX is demonstrated by benchmarking several TDL architectures for various tasks and datasets.

Complex cell signaling systems -- governed by varying protein abundances and interactions -- generate diverse cell types across organs. These systems evolve under influences such as age, sex, diet, environmental exposures, and diseases, making them challenging to decode given the involvement of tens of thousands of genes and proteins. Recently, hundreds of millions of single-cell omics data have provided a robust foundation for understanding these signaling networks within various cell subpopulations and conditions. Inspired by the success of large foundation models (for example, large language models and large vision models) pre-trained on massive datasets, we introduce OmniCellTOSG, the first dataset of cell text-omic signaling graphs (TOSGs). Each TOSG represents the signaling network of an individual or meta-cell and is labeled with information such as organ, disease, sex, age, and cell subtype. OmniCellTOSG offers two key contributions. First, it introduces a novel graph model that integrates human-readable annotations -- such as biological functions, cellular locations, signaling pathways, related diseases, and drugs -- with quantitative gene and protein abundance data, enabling graph reasoning to decode cell signaling. This approach calls for new joint models combining large language models and graph neural networks. Second, the dataset is built from single-cell RNA sequencing data of approximately 120 million cells from diverse tissues and conditions (healthy and diseased) and is fully compatible with PyTorch. This facilitates the development of innovative cell signaling models that could transform research in life sciences, healthcare, and precision medicine. The OmniCellTOSG dataset is continuously expanding and will be updated regularly. The dataset and code are available at https://github.com/FuhaiLiAiLab/OmniCellTOSG.

Modeling cellular states and predicting their responses to perturbations are central challenges in computational biology and the development of virtual cells. Existing foundation models for single-cell transcriptomics provide powerful static representations, but they do not explicitly model the distribution of cellular states for generative simulation. Here, we introduce Lingshu-Cell, a masked discrete diffusion model that learns transcriptomic state distributions and supports conditional simulation under perturbation. By operating directly in a discrete token space that is compatible with the sparse, non-sequential nature of single-cell transcriptomic data, Lingshu-Cell captures complex transcriptome-wide expression dependencies across approximately 18,000 genes without relying on prior gene selection, such as filtering by high variability or ranking by expression level. Across diverse tissues and species, Lingshu-Cell accurately reproduces transcriptomic distributions, marker-gene expression patterns and cell-subtype proportions, demonstrating its ability to capture complex cellular heterogeneity. Moreover, by jointly embedding cell type or donor identity with perturbation, Lingshu-Cell can predict whole-transcriptome expression changes for novel combinations of identity and perturbation. It achieves leading performance on the Virtual Cell Challenge H1 genetic perturbation benchmark and in predicting cytokine-induced responses in human PBMCs. Together, these results establish Lingshu-Cell as a flexible cellular world model for in silico simulation of cell states and perturbation responses, laying the foundation for a new paradigm in biological discovery and perturbation screening.

Gene perturbation analysis plays a critical role in drug discovery by enabling researchers to investigate how interventions on specific genes influence global gene expression patterns within cells. Recent advances in artificial intelligence-driven virtual cell models have made it possible to predict gene expression outcomes for a wide range of perturbation strategies in silico, substantially reducing reliance on costly and time-consuming biological experiments. However, effectively exploring and interpreting the high-dimensional perturbation spaces produced by these models remains challenging because of the combinatorial nature of perturbations and the complex cell-specific gene expression responses they generate. In this work, we present CellPrism, a visual analytics system designed to support the systematic exploration of gene perturbation strategies for drug discovery. Specifically, CellPrism integrates clustering-based overviews to summarize perturbation outcomes, a glyph-based representation to compactly encode gene expression patterns across cell types, and coordinated views that enable fine-grained comparison and interpretation of perturbation effects. We demonstrate the effectiveness of CellPrism through a real-world case study and expert interviews. This work highlights the value of visual analytics in bridging virtual cell modeling with expert-driven decision making in drug discovery.

Predicting cellular responses to perturbations is a central problem in cellular biology, with broad applications in systems biology and drug discovery. This task is challenging because cellular responses can be complex and cell-state dependent, intrinsic cell-to-cell variability can be confounded with perturbation effects, and destructive single-cell RNA sequencing precludes paired measurements of the same cell before and after treatment. Flow matching transports control cells to perturbed states flexibly, but acting on the full cell state can confound perturbation effects with pre-existing cell-to-cell variability. Disentangled approaches separate responsive from invariant components, but model perturbations through prescribed mechanisms, such as latent shifts or graph edits, limiting their flexibility. We address both limitations in a unified framework. A variational encoder disentangles each cell into an invariant block, capturing state unaffected by the perturbation, and a responsive block, capturing state it changes, through conditional priors and an information-theoretic invariance constraint. Conditional flow matching transports only the responsive block, conditioned on the perturbation and invariant state, yielding a flexible, data-driven model of perturbation effects without confounding pre-existing variability. Across several benchmarks, our method outperforms the strongest published method in settings involving combinatorial and unseen perturbation prediction.

Large language models excel at interpreting complex natural language instructions, enabling them to perform a wide range of tasks. In the life sciences, single-cell RNA sequencing (scRNA-seq) data serves as the "language of cellular biology", capturing intricate gene expression patterns at the single-cell level. However, interacting with this "language" through conventional tools is often inefficient and unintuitive, posing challenges for researchers. To address these limitations, we present InstructCell, a multi-modal AI copilot that leverages natural language as a medium for more direct and flexible single-cell analysis. We construct a comprehensive multi-modal instruction dataset that pairs text-based instructions with scRNA-seq profiles from diverse tissues and species. Building on this, we develop a multi-modal cell language architecture capable of simultaneously interpreting and processing both modalities. InstructCell empowers researchers to accomplish critical tasks-such as cell type annotation, conditional pseudo-cell generation, and drug sensitivity prediction-using straightforward natural language commands. Extensive evaluations demonstrate that InstructCell consistently meets or exceeds the performance of existing single-cell foundation models, while adapting to diverse experimental conditions. More importantly, InstructCell provides an accessible and intuitive tool for exploring complex single-cell data, lowering technical barriers and enabling deeper biological insights.

Cell tracking is a ubiquitous image analysis task in live-cell microscopy. Unlike multiple object tracking (MOT) for natural images, cell tracking typically involves hundreds of similar-looking objects that can divide in each frame, making it a particularly challenging problem. Current state-of-the-art approaches follow the tracking-by-detection paradigm, i.e. first all cells are detected per frame and successively linked in a second step to form biologically consistent cell tracks. Linking is commonly solved via discrete optimization methods, which require manual tuning of hyperparameters for each dataset and are therefore cumbersome to use in practice. Here we propose Trackastra, a general purpose cell tracking approach that uses a simple transformer architecture to directly learn pairwise associations of cells within a temporal window from annotated data. Importantly, unlike existing transformer-based MOT pipelines, our learning architecture also accounts for dividing objects such as cells and allows for accurate tracking even with simple greedy linking, thus making strides towards removing the requirement for a complex linking step. The proposed architecture operates on the full spatio-temporal context of detections within a time window by avoiding the computational burden of processing dense images. We show that our tracking approach performs on par with or better than highly tuned state-of-the-art cell tracking algorithms for various biological datasets, such as bacteria, cell cultures and fluorescent particles. We provide code at https://github.com/weigertlab/trackastra.

In this paper, we propose HiPoNet, an end-to-end differentiable neural network for regression, classification, and representation learning on high-dimensional point clouds. Our work is motivated by single-cell data which can have very high-dimensionality --exceeding the capabilities of existing methods for point clouds which are mostly tailored for 3D data. Moreover, modern single-cell and spatial experiments now yield entire cohorts of datasets (i.e., one data set for every patient), necessitating models that can process large, high-dimensional point-clouds at scale. Most current approaches build a single nearest-neighbor graph, discarding important geometric and topological information. In contrast, HiPoNet models the point-cloud as a set of higher-order simplicial complexes, with each particular complex being created using a reweighting of features. This method thus generates multiple constructs corresponding to different views of high-dimensional data, which in biology offers the possibility of disentangling distinct cellular processes. It then employs simplicial wavelet transforms to extract multiscale features, capturing both local and global topology from each view. We show that geometric and topological information is preserved in this framework both theoretically and empirically. We showcase the utility of HiPoNet on point-cloud level tasks, involving classification and regression of entire point-clouds in data cohorts. Experimentally, we find that HiPoNet outperforms other point-cloud and graph-based models on single-cell data. We also apply HiPoNet to spatial transcriptomics datasets using spatial coordinates as one of the views. Overall, HiPoNet offers a robust and scalable solution for high-dimensional data analysis.

Cell migration in vivo is often guided by chemical signals. Such chemotaxis, such as performed by immune cells migrating to a wound site, is complicated by the complex geometry inside living tissues. In this study, we extend our theoretical model of branched-cell migration on a network by introducing chemokine sources to explore the cellular response. The model predicts a speed-accuracy tradeoff, whereby slow cells are significantly more accurate and able to follow efficiently a weak chemoattractant signal. We then compare the model's predictions with experimental observations of neutrophils migrating to the site of laser-inflicted wound in a zebrafish larva fin, and migrating in-vitro inside a regular lattice of pillars. We find that the model captures the details of the sub-cellular response to the chemokine gradient, as well as the large-scale migration response. This comparison suggests that the neutrophils behave as fast cells, compromising their chemotaxis accuracy, which explains the functionality of these immune cells.

Understanding cellular trajectories via time-resolved single-cell transcriptomics is vital for studying development, regeneration, and disease. A key challenge is inferring continuous trajectories from discrete snapshots. Biological complexity stems from stochastic cell fate decisions, temporal proliferation changes, and spatial environmental influences. Current methods often use deterministic interpolations treating cells in isolation, failing to capture the probabilistic branching, population shifts, and niche-dependent signaling driving real biological processes. We introduce Manifold Interpolating Optimal-Transport Flow (MIOFlow) 2.0. This framework learns biologically informed cellular trajectories by integrating manifold learning, optimal transport, and neural differential equations. It models three core processes: (1) stochasticity and branching via Neural Stochastic Differential Equations; (2) non-conservative population changes using a learned growth-rate model initialized with unbalanced optimal transport; and (3) environmental influence through a joint latent space unifying gene expression with spatial features like local cell type composition and signaling. By operating in a PHATE-distance matching autoencoder latent space, MIOFlow 2.0 ensures trajectories respect the data's intrinsic geometry. Empirical comparisons show expressive trajectory learning via neural differential equations outperforms existing generative models, including simulation-free flow matching. Validated on synthetic datasets, embryoid body differentiation, and spatially resolved axolotl brain regeneration, MIOFlow 2.0 improves trajectory accuracy and reveals hidden drivers of cellular transitions, like specific signaling niches. MIOFlow 2.0 thus bridges single-cell and spatial transcriptomics to uncover tissue-scale trajectories.

The segmentation of cell nuclei in tissue images stained with the blood dye hematoxylin and eosin (H&E) is essential for various clinical applications and analyses. Due to the complex characteristics of cellular morphology, a large receptive field is considered crucial for generating high-quality segmentation. However, previous methods face challenges in achieving a balance between the receptive field and computational burden. To address this issue, we propose LKCell, a high-accuracy and efficient cell segmentation method. Its core insight lies in unleashing the potential of large convolution kernels to achieve computationally efficient large receptive fields. Specifically, (1) We transfer pre-trained large convolution kernel models to the medical domain for the first time, demonstrating their effectiveness in cell segmentation. (2) We analyze the redundancy of previous methods and design a new segmentation decoder based on large convolution kernels. It achieves higher performance while significantly reducing the number of parameters. We evaluate our method on the most challenging benchmark and achieve state-of-the-art results (0.5080 mPQ) in cell nuclei instance segmentation with only 21.6% FLOPs compared with the previous leading method. Our source code and models are available at https://github.com/hustvl/LKCell.

Computer-aided histopathological image analysis for cancer detection is a major research challenge in the medical domain. Automatic detection and classification of nuclei for cancer diagnosis impose a lot of challenges in developing state of the art algorithms due to the heterogeneity of cell nuclei and data set variability. Recently, a multitude of classification algorithms has used complex deep learning models for their dataset. However, most of these methods are rigid and their architectural arrangement suffers from inflexibility and non-interpretability. In this research article, we have proposed a hybrid and flexible deep learning architecture OLConvNet that integrates the interpretability of traditional object-level features and generalization of deep learning features by using a shallower Convolutional Neural Network (CNN) named as CNN_{3L}. CNN_{3L} reduces the training time by training fewer parameters and hence eliminating space constraints imposed by deeper algorithms. We used F1-score and multiclass Area Under the Curve (AUC) performance parameters to compare the results. To further strengthen the viability of our architectural approach, we tested our proposed methodology with state of the art deep learning architectures AlexNet, VGG16, VGG19, ResNet50, InceptionV3, and DenseNet121 as backbone networks. After a comprehensive analysis of classification results from all four architectures, we observed that our proposed model works well and perform better than contemporary complex algorithms.

Single-cell RNA-seq (scRNA-seq) enables atlas-scale profiling of complex tissues, revealing rare lineages and transient states. Yet, assigning biologically valid cell identities remains a bottleneck because markers are tissue- and state-dependent, and novel states lack references. We present CellMaster, an AI agent that mimics expert practice for zero-shot cell-type annotation. Unlike existing automated tools, CellMaster leverages LLM-encoded knowledge (e.g., GPT-4o) to perform on-the-fly annotation with interpretable rationales, without pre-training or fixed marker databases. Across 9 datasets spanning 8 tissues, CellMaster improved accuracy by 7.1% over best-performing baselines (including CellTypist and scTab) in automatic mode. With human-in-the-loop refinement, this advantage increased to 18.6%, with a 22.1% gain on subtype populations. The system demonstrates particular strength in rare and novel cell states where baselines often fail. Source code and the web application are available at https://github.com/AnonymousGym/CellMaster{https://github.com/AnonymousGym/CellMaster}.

Predicting the effects of perturbations in-silico on cell state can identify drivers of cell behavior at scale and accelerate drug discovery. However, modeling challenges remain due to the inherent heterogeneity of single cell gene expression and the complex, latent gene dependencies. Here, we present PRiMeFlow, an end-to-end flow matching based approach to directly model the effects of genetic and small molecule perturbations in the gene expression space. The distribution-fitting approach taken by PRiMeFlow enables it to accurately approximate the empirical distribution of single-cell gene expression, which we demonstrate through extensive benchmarking inside PerturBench. Through ablation studies, we also validate important model design choices such as operating in gene expression space and parameterizing the velocity field with a U-Net architecture. Finally, by scaling PRiMeFlow to a broad perturbation data atlas spanning multiple datasets and employing a carefully designed pretraining-finetuning strategy, we demonstrate its outstanding performance on the H1 human embryonic stem cells from the ARC Virtual Cell Challenge benchmark.

We present an algorithmic framework for incremental maintenance of first sheaf cohomology H^1(X; F) on dynamically evolving 1-dimensional cellular complexes equipped with finite-dimensional cellular sheaves. The classical computation of H^1 via factorization of the coboundary matrix requires O(n^3) time; when the complex evolves with a stream of m edits, full recomputation after each edit costs O(mn^3). Under a bounded local geometry assumption -- bounded cell size v_{max}, bounded stalk dimension d, and bounded nerve degree D -- each edit (vertex insertion, edge insertion, restriction map update) affects only a bounded set of local coboundary blocks. The algorithm therefore processes lazy streaming edits in O(1) time with respect to the total complex size n (with cost polynomial in the local geometry parameters v_{max}, d, and D, which are treated as constants independent of n), deferring local eigensolves and Mayer-Vietoris global assembly to synchronization points (Flush). At synchronization, the maintained state agrees with the corresponding batch assembly of the partitioned sheaf model; we observe zero measured drift in all batch-verified runs (through V = 10^6). We also give an amortized O(|E|) streaming construction for the cellular decomposition and discuss an adversarial algebraic-RAM barrier arguing that unpartitioned non-trivial sheaves (d geq 2, non-identity restriction maps) do not admit the same locality. Experiments on Barabasi-Albert graphs with up to 5 times 10^6 vertices and 1.7 times 10^7 streaming edits show 35 μs median lazy per-edit update latency (excluding flush); query time (global assembly at synchronization) is O(n) per flush in the implemented full-traversal path. Exact synchronization costs are reported separately.

With the Generative Pre-trained Transformer 3.5 (GPT-3.5) exhibiting remarkable reasoning and comprehension abilities in Natural Language Processing (NLP), most Question Answering (QA) research has primarily centered around general QA tasks based on GPT, neglecting the specific challenges posed by Complex Table QA. In this paper, we propose to incorporate GPT-3.5 to address such challenges, in which complex tables are reconstructed into tuples and specific prompt designs are employed for dialogues. Specifically, we encode each cell's hierarchical structure, position information, and content as a tuple. By enhancing the prompt template with an explanatory description of the meaning of each tuple and the logical reasoning process of the task, we effectively improve the hierarchical structure awareness capability of GPT-3.5 to better parse the complex tables. Extensive experiments and results on Complex Table QA datasets, i.e., the open-domain dataset HiTAB and the aviation domain dataset AIT-QA show that our approach significantly outperforms previous work on both datasets, leading to state-of-the-art (SOTA) performance.

Time-lapse fluorescent microscopy (TLFM) combined with predictive mathematical modelling is a powerful tool to study the inherently dynamic processes of life on the single-cell level. Such experiments are costly, complex and labour intensive. A complimentary approach and a step towards in silico experimentation, is to synthesise the imagery itself. Here, we propose Multi-StyleGAN as a descriptive approach to simulate time-lapse fluorescence microscopy imagery of living cells, based on a past experiment. This novel generative adversarial network synthesises a multi-domain sequence of consecutive timesteps. We showcase Multi-StyleGAN on imagery of multiple live yeast cells in microstructured environments and train on a dataset recorded in our laboratory. The simulation captures underlying biophysical factors and time dependencies, such as cell morphology, growth, physical interactions, as well as the intensity of a fluorescent reporter protein. An immediate application is to generate additional training and validation data for feature extraction algorithms or to aid and expedite development of advanced experimental techniques such as online monitoring or control of cells. Code and dataset is available at https://git.rwth-aachen.de/bcs/projects/tp/multi-stylegan.

Computational modeling of single-cell gene expression is crucial for understanding cellular processes, but generating realistic expression profiles remains a major challenge. This difficulty arises from the count nature of gene expression data and complex latent dependencies among genes. Existing generative models often impose artificial gene orderings or rely on shallow neural network architectures. We introduce a scalable latent diffusion model for single-cell gene expression data, which we refer to as scLDM, that respects the fundamental exchangeability property of the data. Our VAE uses fixed-size latent variables leveraging a unified Multi-head Cross-Attention Block (MCAB) architecture, which serves dual roles: permutation-invariant pooling in the encoder and permutation-equivariant unpooling in the decoder. We enhance this framework by replacing the Gaussian prior with a latent diffusion model using Diffusion Transformers and linear interpolants, enabling high-quality generation with multi-conditional classifier-free guidance. We show its superior performance in a variety of experiments for both observational and perturbational single-cell data, as well as downstream tasks like cell-level classification.

Recent advances in sequencing technologies have enabled researchers to explore cellular heterogeneity at single-cell resolution. Meanwhile, interpretability has gained prominence parallel to the rapid increase in the complexity and performance of deep learning models. In recent years, topic models have been widely used for interpretable single-cell embedding learning and clustering analysis, which we refer to as single-cell embedded topic models. However, previous studies evaluated the interpretability of the models mainly through qualitative analysis, and these single-cell embedded topic models suffer from the potential problem of interpretation collapse. Furthermore, their neglect of external biological knowledge constrains analytical performance. Here, we present scE2TM, an external knowledge-guided single-cell embedded topic model that provides a high-quality cell embedding and strong interpretation, contributing to comprehensive scRNA-seq data analysis. Our comprehensive evaluation across 20 scRNA-seq datasets demonstrates that scE2TM achieves significant clustering performance gains compared to 7 state-of-the-art methods. In addition, we propose a new interpretability evaluation benchmark that introduces 10 metrics to quantitatively assess the interpretability of single-cell embedded topic models. The results show that the interpretation provided by scE2TM performs encouragingly in terms of diversity and consistency with the underlying biological signals, contributing to a better revealing of the underlying biological mechanisms.

In this paper, we introduce Latent Go-Explore (LGE), a simple and general approach based on the Go-Explore paradigm for exploration in reinforcement learning (RL). Go-Explore was initially introduced with a strong domain knowledge constraint for partitioning the state space into cells. However, in most real-world scenarios, drawing domain knowledge from raw observations is complex and tedious. If the cell partitioning is not informative enough, Go-Explore can completely fail to explore the environment. We argue that the Go-Explore approach can be generalized to any environment without domain knowledge and without cells by exploiting a learned latent representation. Thus, we show that LGE can be flexibly combined with any strategy for learning a latent representation. Our results indicate that LGE, although simpler than Go-Explore, is more robust and outperforms state-of-the-art algorithms in terms of pure exploration on multiple hard-exploration environments including Montezuma's Revenge. The LGE implementation is available as open-source at https://github.com/qgallouedec/lge.

Cellular form and function emerge from complex mechanochemical systems within the cytoplasm. No systematic strategy currently exists to infer large-scale physical properties of a cell from its many molecular components. This is a significant obstacle to understanding biophysical processes such as cell adhesion and migration. Here, we develop a data-driven biophysical modeling approach to learn the mechanical behavior of adherent cells. We first train neural networks to predict forces generated by adherent cells from images of cytoskeletal proteins. Strikingly, experimental images of a single focal adhesion protein, such as zyxin, are sufficient to predict forces and generalize to unseen biological regimes. This protein field alone contains enough information to yield accurate predictions even if forces themselves are generated by many interacting proteins. We next develop two approaches - one explicitly constrained by physics, the other more agnostic - that help construct data-driven continuum models of cellular forces using this single focal adhesion field. Both strategies consistently reveal that cellular forces are encoded by two different length scales in adhesion protein distributions. Beyond adherent cell mechanics, our work serves as a case study for how to integrate neural networks in the construction of predictive phenomenological models in cell biology, even when little knowledge of the underlying microscopic mechanisms exist.

Many cellular processes involve information processing and decision making. We can probe these processes at increasing molecular detail. The analysis of heterogeneous data remains a challenge that requires new ways of thinking about cells in quantitative, predictive, and mechanistic ways. We discuss the role of mathematical models in the context of cell-fate decision making systems across the tree of life. Complex multi-cellular organisms have been a particular focus, but single celled organisms also have to sense and respond to their environment. We center our discussion around the idea of design principles which we can learn from observations and modeling, and exploit in order to (re)-design or guide cellular behavior.

Motivation: The activity of the adaptive immune system is governed by T-cells and their specific T-cell receptors (TCR), which selectively recognize foreign antigens. Recent advances in experimental techniques have enabled sequencing of TCRs and their antigenic targets (epitopes), allowing to research the missing link between TCR sequence and epitope binding specificity. Scarcity of data and a large sequence space make this task challenging, and to date only models limited to a small set of epitopes have achieved good performance. Here, we establish a k-nearest-neighbor (K-NN) classifier as a strong baseline and then propose TITAN (Tcr epITope bimodal Attention Networks), a bimodal neural network that explicitly encodes both TCR sequences and epitopes to enable the independent study of generalization capabilities to unseen TCRs and/or epitopes. Results: By encoding epitopes at the atomic level with SMILES sequences, we leverage transfer learning and data augmentation to enrich the input data space and boost performance. TITAN achieves high performance in the prediction of specificity of unseen TCRs (ROC-AUC 0.87 in 10-fold CV) and surpasses the results of the current state-of-the-art (ImRex) by a large margin. Notably, our Levenshtein-distance-based K-NN classifier also exhibits competitive performance on unseen TCRs. While the generalization to unseen epitopes remains challenging, we report two major breakthroughs. First, by dissecting the attention heatmaps, we demonstrate that the sparsity of available epitope data favors an implicit treatment of epitopes as classes. This may be a general problem that limits unseen epitope performance for sufficiently complex models. Second, we show that TITAN nevertheless exhibits significantly improved performance on unseen epitopes and is capable of focusing attention on chemically meaningful molecular structures.

Single-cell technologies generate high-dimensional point clouds of cells, enabling detailed characterization of complex patient states and treatment responses. Yet each patient is represented by an irregular point cloud rather than a simple vector, making it difficult to directly quantify and compare biological differences between individuals. Nonlinear methods such as kernels and neural networks achieve predictive accuracy but act as black boxes, offering little biological interpretability. To address these limitations, we adapt the Linear Optimal Transport (LOT) framework to this setting, embedding irregular point clouds into a fixed-dimensional Euclidean space while preserving distributional structure. This embedding provides a principled linear representation that preserves optimal transport geometry while enabling downstream analysis. It also forms a registration between any two patients, enabling direct comparison of their cellular distributions. Within this space, LOT enables: (i) accurate and interpretable classification of COVID-19 patient states, where classifier weights map back to specific markers and spatial regions driving predictions; and (ii) synthetic data generation for patient-derived organoids, exploiting the linearity of the LOT embedding. LOT barycenters yield averaged cellular profiles representing combined conditions or samples, supporting drug interaction testing. Together, these results establish LOT as a unified framework that bridges predictive performance, interpretability, and generative modeling. By transforming heterogeneous point clouds into structured embeddings directly traceable to the original data, LOT opens new opportunities for understanding immune variation and treatment effects in high-dimensional biological systems.

Historically, VLSI designers have focused on increasing the speed and reducing the area of digital systems. However, the evolution of portable systems and advanced Deep Sub-Micron fabrication technologies have brought power dissipation as another critical design factor. Low power design reduces cooling cost and increases reliability especially for high density systems. Moreover, it reduces the weight and size of portable devices. The power dissipation in CMOS circuits consists of static and dynamic components. Since dynamic power is proportional to V2 dd and static power is proportional to Vdd, lowering the supply voltage and device dimensions, the transistor threshold voltage also has to be scaled down to achieve the required performance. In case of static power, the power is consumed during the steady state condition i.e when there are no input/output transitions. Static power has two sources: DC power and Leakage power. Consecutively to facilitate voltage scaling without disturbing the performance, threshold voltage has to be minimized. Furthermore it leads to better noise margins and helps to avoid the hot carrier effects in short channel devices. In this paper we have been proposed the new CMOS library for the complex digital design using scaling the supply voltage and device dimensions and also suggest the methods to control the leakage current to obtain the minimum power dissipation at optimum value of supply voltage and transistor threshold. In this paper CMOS Cell library has been implemented using TSMC (0.18um) and TSMC (90nm) technology using HEP2 tool of IC designing from Mentor Graphics for various analysis and simulations.

Transcriptome foundation models TFMs hold great promises of deciphering the transcriptomic language that dictate diverse cell functions by self-supervised learning on large-scale single-cell gene expression data, and ultimately unraveling the complex mechanisms of human diseases. However, current TFMs treat cells as independent samples and ignore the taxonomic relationships between cell types, which are available in cell ontology graphs. We argue that effectively leveraging this ontology information during the TFM pre-training can improve learning biologically meaningful gene co-expression patterns while preserving TFM as a general purpose foundation model for downstream zero-shot and fine-tuning tasks. To this end, we present single cell, Cell-ontology guided TFM scCello. We introduce cell-type coherence loss and ontology alignment loss, which are minimized along with the masked gene expression prediction loss during the pre-training. The novel loss component guide scCello to learn the cell-type-specific representation and the structural relation between cell types from the cell ontology graph, respectively. We pre-trained scCello on 22 million cells from CellxGene database leveraging their cell-type labels mapped to the cell ontology graph from Open Biological and Biomedical Ontology Foundry. Our TFM demonstrates competitive generalization and transferability performance over the existing TFMs on biologically important tasks including identifying novel cell types of unseen cells, prediction of cell-type-specific marker genes, and cancer drug responses.

Collective cell responses to exogenous cues depend on cell-cell interactions. In principle, these can result in enhanced sensitivity to weak and noisy stimuli. However, this has not yet been shown experimentally, and, little is known about how multicellular signal processing modulates single cell sensitivity to extracellular signaling inputs, including those guiding complex changes in the tissue form and function. Here we explored if cell-cell communication can enhance the ability of cell ensembles to sense and respond to weak gradients of chemotactic cues. Using a combination of experiments with mammary epithelial cells and mathematical modeling, we find that multicellular sensing enables detection of and response to shallow Epidermal Growth Factor (EGF) gradients that are undetectable by single cells. However, the advantage of this type of gradient sensing is limited by the noisiness of the signaling relay, necessary to integrate spatially distributed ligand concentration information. We calculate the fundamental sensory limits imposed by this communication noise and combine them with the experimental data to estimate the effective size of multicellular sensory groups involved in gradient sensing. Functional experiments strongly implicated intercellular communication through gap junctions and calcium release from intracellular stores as mediators of collective gradient sensing. The resulting integrative analysis provides a framework for understanding the advantages and limitations of sensory information processing by relays of chemically coupled cells.

Single-cell RNA sequencing (scRNA-seq) enables high-resolution analysis of cellular heterogeneity, but its complexity, which is marked by high dimensionality, sparsity, and batch effects, which poses major computational challenges. Transformer-based models have made significant advances in this domain but are often limited by their quadratic complexity and suboptimal handling of long-range dependencies. In this work, we introduce GeneMamba, a scalable and efficient foundation model for single-cell transcriptomics built on state space modeling. Leveraging the Bi-Mamba architecture, GeneMamba captures bidirectional gene context with linear-time complexity, offering substantial computational gains over transformer baselines. The model is pretrained on nearly 30 million cells and incorporates biologically informed objectives, including pathway-aware contrastive loss and rank-based gene encoding. We evaluate GeneMamba across diverse tasks, including multi-batch integration, cell type annotation, and gene-gene correlation, demonstrating strong performance, interpretability, and robustness. These results position GeneMamba as a practical and powerful alternative to transformer-based methods, advancing the development of biologically grounded, scalable tools for large-scale single-cell data analysis.

Single-cell sequencing technologies reveal cellular heterogeneity at high resolution, advancing our understanding of biological complexity. As datasets start to scale to tens of millions of cells, computational workflows face substantial bottlenecks, with CPU-based analytical pipelines requiring hours or days for routine processing steps like filtering, normalization, and clustering. These scalability limitations fundamentally restrict common interactive data exploration and iterative hypothesis testing. Here we introduce rapids-singlecell, a GPU-accelerated framework that integrates natively with the scverse ecosystem and operates directly on the AnnData data structure, which delivers orders-of-magnitude speedups for single-cell workflows. Built on CuPy arrays and the NVIDIA CUDA-X Data Science (RAPIDS) ecosystem, rapids-singlecell provides near drop-in GPU replacements for core scanpy-based analysis steps. Across standard single-cell workflows such as preprocessing, dimensionality reduction, neighborhood graph construction, clustering, and batch correction, rapids-singlecell achieves speedups of up to several hundred-fold compared to optimized CPU baselines. This reduces analysis time from hours to minutes on standard hardware, while maintaining consistent biological interpretations. These performance improvements make it possible to analyze large data sets in close to real time, without the need for data splitting. Together with real-time parameter tuning and iterative workflows, rapids-singlecell makes interactive large-scale single-cell analysis possible.

Mesogenic materials, quinoxaline derivatives with semi-flexible cores, are reported to form new type of 3D columnar structure with large crystallographic unit cell and Fddd symmetry below columnar hexagonal phase. The 3D columnar structure is a result of frustration imposed by arrangement of helical columns of opposite chirality into triangular lattice. The studied materials exhibit fluorescent properties that could be easily tuned by modification of molecular structure, compounds with the extended {\pi} electron conjugated systems form aggregates and fluorescence is quenched. For molecules with flexible structure the fluorescence quantum yield reaches 25%. On the other hand, compounds with more rigid mesogenic core, for which fluorescence is suppressed show strong hole photocurrent. For some materials also bi-polar: hole and electron transfer was observed.

Over the past decade, the revolution in single-cell sequencing has enabled the simultaneous molecular profiling of various modalities across thousands of individual cells, allowing scientists to investigate the diverse functions of complex tissues and uncover underlying disease mechanisms. Among all the analytical steps, assigning individual cells to specific types is fundamental for understanding cellular heterogeneity. However, this process is usually labor-intensive and requires extensive expert knowledge. Recent advances in large language models (LLMs) have demonstrated their ability to efficiently process and synthesize vast corpora of text to automatically extract essential biological knowledge, such as marker genes, potentially promoting more efficient and automated cell type annotations. To thoroughly evaluate the capability of modern instruction-tuned LLMs in automating the cell type identification process, we introduce SOAR, a comprehensive benchmarking study of LLMs for cell type annotation tasks in single-cell genomics. Specifically, we assess the performance of 8 instruction-tuned LLMs across 11 datasets, spanning multiple cell types and species. Our study explores the potential of LLMs to accurately classify and annotate cell types in single-cell RNA sequencing (scRNA-seq) data, while extending their application to multiomics data through cross-modality translation. Additionally, we evaluate the effectiveness of chain-of-thought (CoT) prompting techniques in generating detailed biological insights during the annotation process. The results demonstrate that LLMs can provide robust interpretations of single-cell data without requiring additional fine-tuning, advancing the automation of cell type annotation in genomics research.

Complex Question Answering (QA) is a fundamental and challenging task in NLP. While large language models (LLMs) exhibit impressive performance in QA, they suffer from significant performance degradation when facing complex and abstract QA tasks due to insufficient reasoning capabilities. Works such as Chain-of-Thought (CoT) and Tree-of-Thought (ToT) aim to enhance LLMs' reasoning abilities, but they face issues such as in-layer redundancy in tree structures and single paths in chain structures. Although some studies utilize Retrieval-Augmented Generation (RAG) methods to assist LLMs in reasoning, the challenge of effectively utilizing large amounts of information involving multiple entities and hops remains critical. To address this, we propose the Matrix of Thought (MoT), a novel and efficient LLM thought structure. MoT explores the problem in both horizontal and vertical dimensions through the "column-cell communication" mechanism, enabling LLMs to actively engage in multi-strategy and deep-level thinking, reducing redundancy within the column cells and enhancing reasoning capabilities. Furthermore, we develop a fact-correction mechanism by constructing knowledge units from retrieved knowledge graph triples and raw text to enhance the initial knowledge for LLM reasoning and correct erroneous answers. This leads to the development of an efficient and accurate QA framework (MTQA). Experimental results show that our framework outperforms state-of-the-art methods on four widely-used datasets in terms of F1 and EM scores, with reasoning time only 14.4\% of the baseline methods, demonstrating both its efficiency and accuracy. The code for this framework is available at https://github.com/lyfiter/mtqa.

Organic crystal structure prediction (CSP) is a requirement for computational modelling of organic solids, but traditionally costs several CPU-years per molecule. Generative models such as OXtal dramatically reduce this cost by sampling stable organic crystal structures directly. However, OXtal forgoes explicit lattice parametrization in favour of modelling large crops of the bulk material with expensive triangle layers, which can incur a computational cost of minutes per molecule. In this paper, we reduce this to seconds with Clari, a large-scale flow matching model that generates redundancy-free unit cells and replaces triangle layers with pure pair-bias attention. Clari requires only atom types and bonds as input and does not need an RDKit-sanitizable input molecule, which expands its applicability to challenging chemistries such as fullerenes, metal complexes, and atom clusters. We further ablate key design choices such as auxiliary losses, timestep distributions, noise priors, and self-conditioning. On OXtal's test sets, we surpass OXtal's solve rate while obtaining a speedup of 15-30times. Because Clari also models explicit hydrogens, it supports inference-time scaling via direct energy ranking, without any decoration or relaxation step. When generating 150 crystals and selecting the top-30 by energy, we further improve solve rate while maintaining a speedup of 5-8times. We also introduce the CSD Teaching Subset as a new test split of diverse and complex molecules for future benchmarking. Our contributions enable CSP within seconds, making large-scale virtual screening of organic solids practical. Code is available at https://github.com/aspuru-guzik-group/clari.

Despite recent interest in open domain question answering (ODQA) over tables, many studies still rely on datasets that are not truly optimal for the task with respect to utilizing structural nature of table. These datasets assume answers reside as a single cell value and do not necessitate exploring over multiple cells such as aggregation, comparison, and sorting. Thus, we release Open-WikiTable, the first ODQA dataset that requires complex reasoning over tables. Open-WikiTable is built upon WikiSQL and WikiTableQuestions to be applicable in the open-domain setting. As each question is coupled with both textual answers and SQL queries, Open-WikiTable opens up a wide range of possibilities for future research, as both reader and parser methods can be applied. The dataset and code are publicly available.

A new method of analyzing grid, or aliasing, instabilities is described, in particle-in-cell (PIC) codes for plasma kinetic theory. It starts with a meshfree approach with N_{p} macroparticles, with N_{p}<infty. Linearization of these equations is done about a uniform density non-drifting equilibrium prescribed by macroparticles on a uniform lattice. Macroparticle positions perturbations are induced about this lattice. The resulting linear equations are analyzed for stability and dispersion relations. The linearized equations are then discretized on a grid of N_{g} points with N_{g} le N_{p}, in both momentum conserving (MCP) and energy conserving (ECP) formulations. For a cold stationary plasma, this leads a dynamical matrix. For ECP, the matrix is symmetric and positive definite (SPD) and immediately shows stability. For MCP, the dynamical matrix is neither symmetric nor positive definite, preventing immediate conclusions on stability. For both MCP and ECP and for a cold stationary plasma, the resulting matrix elements vary relative to the meshfree value, a result of aliasing. This deviation is periodic in the displacement of the particle lattice relative to the grid. In the MCP discretization, eigenvalues occur in complex conjugate pairs for general placement of the particle lattice relative to the grid. These conjugate pairs indicate nonnegative growth rates. The nature of the aliasing is studied and shown to be related to the trapezoidal rule error over the grid. The scaling of the linear growth rates with respect to N_{g} and especially with respect to N_{ppc} is studied. These analytical results are compared with PIC simulations and found to be in excellent agreement. The connection with a cold drifting beam is discussed briefly, specifically, grid-induced instabilities for both the MCP and ECP.

White blood cell (WBC) classification assists in assessing immune health and diagnosing various diseases, yet manual classification is labor-intensive and prone to inconsistencies. Recent advancements in deep learning have shown promise over traditional methods; however, challenges such as data imbalance and the computational demands of modern technologies, such as Transformer-based models which do not scale well with input size, limit their practical application. This paper introduces a novel framework that leverages Mamba models integrated with ensemble learning to improve WBC classification. Mamba models, known for their linear complexity, provide a scalable alternative to Transformer-based approaches, making them suitable for deployment in resource-constrained environments. Additionally, we introduce a new WBC dataset, Chula-WBC-8, for benchmarking. Our approach not only validates the effectiveness of Mamba models in this domain but also demonstrates their potential to significantly enhance classification efficiency without compromising accuracy. The source code can be found at https://github.com/LewisClifton/Mamba-WBC-Classification.

Predicting single-cell transcriptional responses to genetic, chemical and cytokine perturbations is a fundamental challenge in computational biology and AI Virtual Cell (AIVC) modeling, with direct implications for drug discovery and the elucidation of gene regulatory networks. Existing approaches often rely on auxiliary cell-state encoders, hierarchical variational autoencoders, dedicated Transformer encoder-decoder modules, or gene-interaction priors to compress high-dimensional expression profiles into latent representations. While effective, these designs increase architectural complexity and may limit scalability and generalizability. This paper introduces OCOO-T, a minimalist flow-matching-based AIVC model for transcriptional perturbation response prediction. OCOO-T utilizes a vanilla Transformer stack that operates directly on continuous gene expression profiles and formulates perturbation response prediction as a continuous-time denoising process. Perturbation embeddings, dosage information, and cell-line/cell-type specificity are integrated through adaptive layer normalization and in-context tokens. Comprehensive evaluations on Tahoe100M, Replogle, and PBMC benchmarks demonstrate that OCOO-T achieves state-of-the-art performance across diverse perturbations and cell types while effectively scaling to long transcriptional profiles through patching and depatching of cellular contexts. By leveraging the simplicity of Transformer-based denoising for single-cell omics, OCOO-T provides an effective and scalable framework for in-silico cellular simulation.

Building Virtual Cells that can accurately simulate cellular responses to perturbations is a long-standing goal in systems biology. A fundamental challenge is that high-throughput single-cell sequencing is destructive: the same cell cannot be observed both before and after a perturbation. Thus, perturbation prediction requires mapping unpaired control and perturbed populations. Existing models address this by learning maps between distributions, but typically assume a single fixed response distribution when conditioned on observed cellular context (e.g., cell type) and the perturbation type. In reality, responses vary systematically due to unobservable latent factors such as microenvironmental fluctuations and complex batch effects, forming a manifold of possible distributions for the same observed conditions. To account for this variability, we introduce PerturbDiff, which shifts modeling from individual cells to entire distributions. By embedding distributions as points in a Hilbert space, we define a diffusion-based generative process operating directly over probability distributions. This allows PerturbDiff to capture population-level response shifts across hidden factors. Benchmarks on established datasets show that PerturbDiff achieves state-of-the-art performance in single-cell response prediction and generalizes substantially better to unseen perturbations. See our project page (https://katarinayuan.github.io/PerturbDiff-ProjectPage/), where code and data will be made publicly available (https://github.com/DeepGraphLearning/PerturbDiff).

Understanding cell cycle dynamics is crucial for studying biological processes such as growth, development and disease progression. While fluorescent protein reporters like the Fucci system allow live monitoring of cell cycle phases, they require genetic engineering and occupy additional fluorescence channels, limiting broader applicability in complex experiments. In this study, we conduct a comprehensive evaluation of deep learning methods for predicting continuous Fucci signals using non-fluorescence brightfield imaging, a widely available label-free modality. To that end, we generated a large dataset of 1.3 M images of dividing RPE1 cells with full cell cycle trajectories to quantitatively compare the predictive performance of distinct model categories including single time-frame models, causal state space models and bidirectional transformer models. We show that both causal and transformer-based models significantly outperform single- and fixed frame approaches, enabling the prediction of visually imperceptible transitions like G1/S within 1h resolution. Our findings underscore the importance of sequence models for accurate predictions of cell cycle dynamics and highlight their potential for label-free imaging.

Virtual cell modeling represents an emerging frontier at the intersection of artificial intelligence and biology, aiming to predict quantities such as responses to diverse perturbations quantitatively. However, autonomously building computational models for virtual cells is challenging due to the complexity of biological systems, the heterogeneity of data modalities, and the need for domain-specific expertise across multiple disciplines. Here, we introduce CellForge, an agentic system that leverages a multi-agent framework that transforms presented biological datasets and research objectives directly into optimized computational models for virtual cells. More specifically, given only raw single-cell multi-omics data and task descriptions as input, CellForge outputs both an optimized model architecture and executable code for training virtual cell models and inference. The framework integrates three core modules: Task Analysis for presented dataset characterization and relevant literature retrieval, Method Design, where specialized agents collaboratively develop optimized modeling strategies, and Experiment Execution for automated generation of code. The agents in the Design module are separated into experts with differing perspectives and a central moderator, and have to collaboratively exchange solutions until they achieve a reasonable consensus. We demonstrate CellForge's capabilities in single-cell perturbation prediction, using six diverse datasets that encompass gene knockouts, drug treatments, and cytokine stimulations across multiple modalities. CellForge consistently outperforms task-specific state-of-the-art methods. Overall, CellForge demonstrates how iterative interaction between LLM agents with differing perspectives provides better solutions than directly addressing a modeling challenge. Our code is publicly available at https://github.com/gersteinlab/CellForge.

As single-cell RNA sequencing datasets grow in adoption, scale, and complexity, data analysis remains a bottleneck for many research groups. Although frontier AI agents have improved dramatically at software engineering and general data analysis, it remains unclear whether they can extract biological insight from messy, real-world single-cell datasets. We introduce scBench, a benchmark of 394 verifiable problems derived from practical scRNA-seq workflows spanning six sequencing platforms and seven task categories. Each problem provides a snapshot of experimental data immediately prior to an analysis step and a deterministic grader that evaluates recovery of a key biological result. Benchmark data on eight frontier models shows that accuracy ranges from 29-53%, with strong model-task and model-platform interactions. Platform choice affects accuracy as much as model choice, with 40+ percentage point drops on less-documented technologies. scBench complements SpatialBench to cover the two dominant single-cell modalities, serving both as a measurement tool and a diagnostic lens for developing agents that can analyze real scRNA-seq datasets faithfully and reproducibly.

Virtual cell (VC) models aim to predict cellular responses to any perturbations in silico and have emerged as a promising approach for drug discovery and precision medicine. Yet, a clear gap still remains: while models routinely reported impressive results on standard benchmarks, it is unclear whether their predictions are truly meaningful in practice. This is mainly due to limitations in current evaluation setups, which are often overly simplified or inconsistent, and do not reflect the complexity and variability of real biological systems. Here, we introduce a standardized and modular benchmarking framework for virtual cell prediction. Our framework evaluates diverse models under in-the-wild challenging scenarios, including unseen cell contexts, unseen perturbations, and cross-dataset generalization, which better reflect practical applications. Our analysis shows that model performance is highly context-dependent and shaped by task design and evaluation criteria. In commonly used setups, performance is often overestimated, and naive dataset aggregation can even reduce performance. When evaluated under more strict conditions, model performance drops markedly, indicating limited robustness to shifts across cellular contexts. In unseen perturbation settings, models including simple linear approaches capture global transcriptional trends but fail to recover fine-grained perturbation-specific effects. In addition, different evaluation metrics focus on different biological properties, leading to substantially different model rankings. Together, our framework provides a more reliable and biologically grounded evaluation, offering clearer guidance for applying virtual cell models in real scenarios.

Identifying cell types and understanding their functional properties is crucial for unraveling the mechanisms underlying perception and cognition. In the retina, functional types can be identified by carefully selected stimuli, but this requires expert domain knowledge and biases the procedure towards previously known cell types. In the visual cortex, it is still unknown what functional types exist and how to identify them. Thus, for unbiased identification of the functional cell types in retina and visual cortex, new approaches are needed. Here we propose an optimization-based clustering approach using deep predictive models to obtain functional clusters of neurons using Most Discriminative Stimuli (MDS). Our approach alternates between stimulus optimization with cluster reassignment akin to an expectation-maximization algorithm. The algorithm recovers functional clusters in mouse retina, marmoset retina and macaque visual area V4. This demonstrates that our approach can successfully find discriminative stimuli across species, stages of the visual system and recording techniques. The resulting most discriminative stimuli can be used to assign functional cell types fast and on the fly, without the need to train complex predictive models or show a large natural scene dataset, paving the way for experiments that were previously limited by experimental time. Crucially, MDS are interpretable: they visualize the distinctive stimulus patterns that most unambiguously identify a specific type of neuron.

As a powerful tool for characterizing cellular subpopulations and cellular heterogeneity, single cell RNA sequencing (scRNA-seq) technology offers advantages of high throughput and multidimensional analysis. However, the process of data acquisition is often constrained by high cost and limited sample availability. To overcome these limitations, we propose a hybrid model based on Diffusion model and White-Box transformer that aims to generate synthetic and biologically plausible scRNA-seq data. Diffusion model progressively introduce noise into the data and then recover the original data through a denoising process, a forward and reverse process that is particularly suitable for generating complex data distributions. White-Box transformer is a deep learning architecture that emphasizes mathematical interpretability. By minimizing the encoding rate of the data and maximizing the sparsity of the representation, it not only reduces the computational burden, but also provides clear insight into underlying structure. Our White-Box Diffusion Transformer combines the generative capabilities of Diffusion model with the mathematical interpretability of White-Box transformer. Through experiments using six different single-cell RNA-Seq datasets, we visualize both generated and real data using t-SNE dimensionality reduction technique, as well as quantify similarity between generated and real data using various metrics to demonstrate comparable performance of White-Box Diffusion Transformer and Diffusion Transformer in generating scRNA-seq data alongside significant improvements in training efficiency and resource utilization. Our code is available at https://github.com/lingximamo/White-Box-Diffusion-Transformer

Nanorobots are a promising development in targeted drug delivery and the treatment of neurological disorders, with potential for crossing the blood-brain barrier (BBB). These small devices leverage advancements in nanotechnology and bioengineering for precise navigation and targeted payload delivery, particularly for conditions like brain tumors, Alzheimer's disease, and Parkinson's disease. Recent progress in artificial intelligence (AI) and machine learning (ML) has improved the navigation and effectiveness of nanorobots, allowing them to detect and interact with cancer cells through biomarker analysis. This study presents a new reinforcement learning (RL) framework for optimizing nanorobot navigation in complex biological environments, focusing on cancer cell detection by analyzing the concentration gradients of surrounding biomarkers. We utilize a computer simulation model to explore the behavior of nanorobots in a three-dimensional space with cancer cells and biological barriers. The proposed method uses Q-learning to refine movement strategies based on real-time biomarker concentration data, enabling nanorobots to autonomously navigate to cancerous tissues for targeted drug delivery. This research lays the groundwork for future laboratory experiments and clinical applications, with implications for personalized medicine and less invasive cancer treatments. The integration of intelligent nanorobots could revolutionize therapeutic strategies, reducing side effects and enhancing treatment effectiveness for cancer patients. Further research will investigate the practical deployment of these technologies in medical settings, aiming to unlock the full potential of nanorobotics in healthcare.

Large language models (LLMs) are transforming cellular biology by enabling the development of "virtual cells"--computational systems that represent, predict, and reason about cellular states and behaviors. This work provides a comprehensive review of LLMs for virtual cell modeling. We propose a unified taxonomy that organizes existing methods into two paradigms: LLMs as Oracles, for direct cellular modeling, and LLMs as Agents, for orchestrating complex scientific tasks. We identify three core tasks--cellular representation, perturbation prediction, and gene regulation inference--and review their associated models, datasets, evaluation benchmarks, as well as the critical challenges in scalability, generalizability, and interpretability.

The rapid advancement of perovskite solar cells (PSCs) has led to an exponential growth in research publications, creating an urgent need for efficient knowledge management and reasoning systems in this domain. We present a comprehensive knowledge-enhanced system for PSCs that integrates three key components. First, we develop Perovskite-KG, a domain-specific knowledge graph constructed from 1,517 research papers, containing 23,789 entities and 22,272 relationships. Second, we create two complementary datasets: Perovskite-Chat, comprising 55,101 high-quality question-answer pairs generated through a novel multi-agent framework, and Perovskite-Reasoning, containing 2,217 carefully curated materials science problems. Third, we introduce two specialized large language models: Perovskite-Chat-LLM for domain-specific knowledge assistance and Perovskite-Reasoning-LLM for scientific reasoning tasks. Experimental results demonstrate that our system significantly outperforms existing models in both domain-specific knowledge retrieval and scientific reasoning tasks, providing researchers with effective tools for literature review, experimental design, and complex problem-solving in PSC research.

Single-cell RNA sequencing (scRNA-seq) data analysis is crucial for biological research, as it enables the precise characterization of cellular heterogeneity. However, manual manipulation of various tools to achieve desired outcomes can be labor-intensive for researchers. To address this, we introduce CellAgent (http://cell.agent4science.cn/), an LLM-driven multi-agent framework, specifically designed for the automatic processing and execution of scRNA-seq data analysis tasks, providing high-quality results with no human intervention. Firstly, to adapt general LLMs to the biological field, CellAgent constructs LLM-driven biological expert roles - planner, executor, and evaluator - each with specific responsibilities. Then, CellAgent introduces a hierarchical decision-making mechanism to coordinate these biological experts, effectively driving the planning and step-by-step execution of complex data analysis tasks. Furthermore, we propose a self-iterative optimization mechanism, enabling CellAgent to autonomously evaluate and optimize solutions, thereby guaranteeing output quality. We evaluate CellAgent on a comprehensive benchmark dataset encompassing dozens of tissues and hundreds of distinct cell types. Evaluation results consistently show that CellAgent effectively identifies the most suitable tools and hyperparameters for single-cell analysis tasks, achieving optimal performance. This automated framework dramatically reduces the workload for science data analyses, bringing us into the "Agent for Science" era.

Generating realistic synthetic microscopy images is critical for training deep learning models in label-scarce environments, such as cell counting with many cells per image. However, traditional domain adaptation methods often struggle to bridge the domain gap when synthetic images lack the complex textures and visual patterns of real samples. In this work, we adapt the Inversion-Based Style Transfer (InST) framework originally designed for artistic style transfer to biomedical microscopy images. Our method combines latent-space Adaptive Instance Normalization with stochastic inversion in a diffusion model to transfer the style from real fluorescence microscopy images to synthetic ones, while weakly preserving content structure. We evaluate the effectiveness of our InST-based synthetic dataset for downstream cell counting by pre-training and fine-tuning EfficientNet-B0 models on various data sources, including real data, hard-coded synthetic data, and the public Cell200-s dataset. Models trained with our InST-synthesized images achieve up to 37\% lower Mean Absolute Error (MAE) compared to models trained on hard-coded synthetic data, and a 52\% reduction in MAE compared to models trained on Cell200-s (from 53.70 to 25.95 MAE). Notably, our approach also outperforms models trained on real data alone (25.95 vs. 27.74 MAE). Further improvements are achieved when combining InST-synthesized data with lightweight domain adaptation techniques such as DACS with CutMix. These findings demonstrate that InST-based style transfer most effectively reduces the domain gap between synthetic and real microscopy data. Our approach offers a scalable path for enhancing cell counting performance while minimizing manual labeling effort. The source code and resources are publicly available at: https://github.com/MohammadDehghan/InST-Microscopy.

Tables are pervasive in diverse documents, making table recognition (TR) a fundamental task in document analysis. Existing modular TR pipelines separately model table structure and content, leading to suboptimal integration and complex workflows. End-to-end approaches rely heavily on large-scale TR data and struggle in data-constrained scenarios. To address these issues, we propose TDATR (Table Detail-Aware Table Recognition) improves end-to-end TR through table detail-aware learning and cell-level visual alignment. TDATR adopts a ``perceive-then-fuse'' strategy. The model first performs table detail-aware learning to jointly perceive table structure and content through multiple structure understanding and content recognition tasks designed under a language modeling paradigm. These tasks can naturally leverage document data from diverse scenarios to enhance model robustness. The model then integrates implicit table details to generate structured HTML outputs, enabling more efficient TR modeling when trained with limited data. Furthermore, we design a structure-guided cell localization module integrated into the end-to-end TR framework, which efficiently locates cell and strengthens vision-language alignment. It enhances the interpretability and accuracy of TR. We achieve state-of-the-art or highly competitive performance on seven benchmarks without dataset-specific fine-tuning.

Large language models (LLMs) are increasingly applied in scientific research, offering new capabilities for knowledge discovery and reasoning. In single-cell biology, however, evaluation practices for both general and specialized LLMs remain inadequate: existing benchmarks are fragmented across tasks, adopt formats such as multiple-choice classification that diverge from real-world usage, and rely on metrics lacking interpretability and biological grounding. We present SC-ARENA, a natural language evaluation framework tailored to single-cell foundation models. SC-ARENA formalizes a virtual cell abstraction that unifies evaluation targets by representing both intrinsic attributes and gene-level interactions. Within this paradigm, we define five natural language tasks (cell type annotation, captioning, generation, perturbation prediction, and scientific QA) that probe core reasoning capabilities in cellular biology. To overcome the limitations of brittle string-matching metrics, we introduce knowledge-augmented evaluation, which incorporates external ontologies, marker databases, and scientific literature to support biologically faithful and interpretable judgments. Experiments and analysis across both general-purpose and domain-specialized LLMs demonstrate that (i) under the Virtual Cell unified evaluation paradigm, current models achieve uneven performance on biologically complex tasks, particularly those demanding mechanistic or causal understanding; and (ii) our knowledge-augmented evaluation framework ensures biological correctness, provides interpretable, evidence-grounded rationales, and achieves high discriminative capacity, overcoming the brittleness and opacity of conventional metrics. SC-Arena thus provides a unified and interpretable framework for assessing LLMs in single-cell biology, pointing toward the development of biology-aligned, generalizable foundation models.

Evaluating machine learning in scientific domains requires separating correct predictions from correct reasons under realistic distribution shifts. We introduce PertReason, a knowledge-grounded benchmark and framework suite for cell-state--conditioned reasoning about perturbation effects. At its core, PertReasonQA is a benchmark that tests whether models can generate mechanistically faithful explanations while remaining robust to complex shifts, such as new cells and unseen perturbations. PertReasonQA combines single-cell genetic and chemical perturbation data across multiple cellular contexts with knowledge graphs, and dynamically conditions pathways on cell-specific basal states to avoid generic memorization. Evaluations on state-of-the-art models reveal systematic gaps between predictive accuracy and mechanistic reasoning. Specifically, these models exhibit failure modes largely invisible to standard benchmarks, such as deriving correct answers through flawed logic, ignoring cellular context, and generating directionally inconsistent mechanisms. As a reference probe of the benchmark, we present PertReasonLM, a large language model trained to align outcome predictions with context-specific mechanistic reasoning. Our model targets the identified failure modes by grounding rationales in context-specific pathways and tightening agreement between outcomes and mechanisms. Together, we provide a diagnostic framework for exposing and mitigating failures in faithful reasoning in data-rich scientific systems.

Cell and nucleus segmentation are fundamental tasks for quantitative bioimage analysis. Despite progress in recent years, biologists and other domain experts still require novel algorithms to handle increasingly large and complex real-world datasets. These algorithms must not only achieve state-of-the-art accuracy, but also be optimized for efficiency, portability and user-friendliness. Here, we introduce InstanSeg: a novel embedding-based instance segmentation pipeline designed to identify cells and nuclei in microscopy images. Using six public cell segmentation datasets, we demonstrate that InstanSeg can significantly improve accuracy when compared to the most widely used alternative methods, while reducing the processing time by at least 60%. Furthermore, InstanSeg is designed to be fully serializable as TorchScript and supports GPU acceleration on a range of hardware. We provide an open-source implementation of InstanSeg in Python, in addition to a user-friendly, interactive QuPath extension for inference written in Java. Our code and pre-trained models are available at https://github.com/instanseg/instanseg .

Handover measurement is responsible for finding a handover target and directly decides the performance of mobility management. It is governed by a complex combination of parameters dealing with multi-cell scenarios and system dynamics. A network design has to offer an appropriate handover measurement procedure in such a multi-constraint problem. The present paper proposes a unified framework for the network analysis and optimization. The exposition focuses on the stochastic modeling and addresses its key probabilistic events namely (i) suitable handover target found, (ii) service failure, (iii) handover measurement triggering, and (iv) handover measurement withdrawal. We derive their closed-form expressions and provide a generalized setup for the analysis of handover measurement failure and target cell quality by the best signal quality and minimum duration outage level crossing properties. Finally, we show its application and effectiveness in today's 3GPP-LTE cellular networks.

The integration of multi-omics single-cell data remains challenging due to high-dimensionality and complex inter-modality relationships. To address this, we introduce MoRE-GNN (Multi-omics Relational Edge Graph Neural Network), a heterogeneous graph autoencoder that combines graph convolution and attention mechanisms to dynamically construct relational graphs directly from data. Evaluations on six publicly available datasets demonstrate that MoRE-GNN captures biologically meaningful relationships and outperforms existing methods, particularly in settings with strong inter-modality correlations. Furthermore, the learned representations allow for accurate downstream cross-modal predictions. While performance may vary with dataset complexity, MoRE-GNN offers an adaptive, scalable and interpretable framework for advancing multi-omics integration.

The regulation of various cellular processes heavily relies on the protein complexes within a living cell, necessitating a comprehensive understanding of their three-dimensional structures to elucidate the underlying mechanisms. While neural docking techniques have exhibited promising outcomes in binary protein docking, the application of advanced neural architectures to multimeric protein docking remains uncertain. This study introduces SyNDock, an automated framework that swiftly assembles precise multimeric complexes within seconds, showcasing performance that can potentially surpass or be on par with recent advanced approaches. SyNDock possesses several appealing advantages not present in previous approaches. Firstly, SyNDock formulates multimeric protein docking as a problem of learning global transformations to holistically depict the placement of chain units of a complex, enabling a learning-centric solution. Secondly, SyNDock proposes a trainable two-step SE(3) algorithm, involving initial pairwise transformation and confidence estimation, followed by global transformation synchronization. This enables effective learning for assembling the complex in a globally consistent manner. Lastly, extensive experiments conducted on our proposed benchmark dataset demonstrate that SyNDock outperforms existing docking software in crucial performance metrics, including accuracy and runtime. For instance, it achieves a 4.5% improvement in performance and a remarkable millionfold acceleration in speed.

This paper presents a mathematical framework for optimizing drug delivery in cancer treatment using a nonlocal model of solid tumor growth. We present a coupled system of partial differential equations that incorporate long-range cellular interactions through integral terms and drug-induced cell death. The model accounts for spatial heterogeneity in both tumor cell density and drug concentration while capturing the complex dynamics of drug resistance development. We first establish the well-posedness of the coupled system by proving the existence and uniqueness of a solution under appropriate regularity conditions. The optimal control problem is then formulated to minimize tumor size while accounting for drug toxicity constraints. Using variational methods, we derive the necessary optimality conditions and characterize the optimal control through an adjoint system. Theoretical results can help to design effective chemotherapy schedules that balance treatment efficacy with adverse effects.

Histopathological analysis is a cornerstone of cancer diagnosis, with Hematoxylin and Eosin (H&E) staining routinely acquired for every patient to visualize cell morphology and tissue architecture. On the other hand, multiplex immunofluorescence (mIF) enables more precise cell type identification via proteomic markers, but has yet to achieve widespread clinical adoption due to cost and logistical constraints. To bridge this gap, we introduce MIPHEI (Multiplex Immunofluorescence Prediction from H&E), a U-Net-inspired architecture that integrates state-of-the-art ViT foundation models as encoders to predict mIF signals from H&E images. MIPHEI targets a comprehensive panel of markers spanning nuclear content, immune lineages (T cells, B cells, myeloid), epithelium, stroma, vasculature, and proliferation. We train our model using the publicly available ORION dataset of restained H&E and mIF images from colorectal cancer tissue, and validate it on two independent datasets. MIPHEI achieves accurate cell-type classification from H&E alone, with F1 scores of 0.88 for Pan-CK, 0.57 for CD3e, 0.56 for SMA, 0.36 for CD68, and 0.30 for CD20, substantially outperforming both a state-of-the-art baseline and a random classifier for most markers. Our results indicate that our model effectively captures the complex relationships between nuclear morphologies in their tissue context, as visible in H&E images and molecular markers defining specific cell types. MIPHEI offers a promising step toward enabling cell-type-aware analysis of large-scale H&E datasets, in view of uncovering relationships between spatial cellular organization and patient outcomes.

In this work, we address the task of table image to LaTeX code generation, with the goal of automating the reconstruction of high-quality, publication-ready tables from visual inputs. A central challenge of this task lies in accurately handling complex tables -- those with large sizes, deeply nested structures, and semantically rich or irregular cell content -- where existing methods often fail. We begin with a comprehensive analysis, identifying key challenges and highlighting the limitations of current evaluation protocols. To overcome these issues, we propose a reinforced multimodal large language model (MLLM) framework, where a pre-trained MLLM is fine-tuned on a large-scale table-to-LaTeX dataset. To further improve generation quality, we introduce a dual-reward reinforcement learning strategy based on Group Relative Policy Optimization (GRPO). Unlike standard approaches that optimize purely over text outputs, our method incorporates both a structure-level reward on LaTeX code and a visual fidelity reward computed from rendered outputs, enabling direct optimization of the visual output quality. We adopt a hybrid evaluation protocol combining TEDS-Structure and CW-SSIM, and show that our method achieves state-of-the-art performance, particularly on structurally complex tables, demonstrating the effectiveness and robustness of our approach.

Drug-target interaction (DTI) prediction is crucial for identifying new therapeutics and detecting mechanisms of action. While structure-based methods accurately model physical interactions between a drug and its protein target, cell-based assays such as Cell Painting can better capture complex DTI interactions. This paper introduces MOTIVE, a Morphological cOmpound Target Interaction Graph dataset that comprises Cell Painting features for 11,000 genes and 3,600 compounds along with their relationships extracted from seven publicly available databases. We provide random, cold-source (new drugs), and cold-target (new genes) data splits to enable rigorous evaluation under realistic use cases. Our benchmark results show that graph neural networks that use Cell Painting features consistently outperform those that learn from graph structure alone, feature-based models, and topological heuristics. MOTIVE accelerates both graph ML research and drug discovery by promoting the development of more reliable DTI prediction models. MOTIVE resources are available at https://github.com/carpenter-singh-lab/motive.

Predicting transcriptomic responses to small-molecule perturbations across cell lines is central to drug discovery, but exhaustive profiling of drug-cell combinations is infeasible. We frame molecular perturbation prediction as retrieve-and-aggregate: approximate an unmeasured drug's response in a cell line by aggregating measured responses of a small set of biologically related compounds. We propose LLM-Guided Retrieval (LGR), where a large language model (LLM) ranks candidate neighbor drugs (restricted to those profiled in the target cell line); after which a fixed mean aggregator combines their observed expression deltas to form the prediction. We evaluate on the Tahoe-100M single-cell perturbation atlas under unseen-drug, unseen-cell-line, and open-world regimes. LGR consistently improves over drug mean, ChemCPA, and chemistry-based kNN baselines, with the strongest gains for unseen cell-line generalization, where it achieves higher correlation and lower error than mean baselines. Across settings, LGR improves directional (sign) accuracy of gene regulation, indicating better recovery of biologically meaningful perturbation effects even when magnitude-based metrics are similar. These results suggest that retrieval quality, rather than predictor complexity, is a key driver of zero-shot molecular perturbation prediction, and that LLMs can provide a useful biological prior when used as constrained retrieval modules.

Precise and scalable instance segmentation of cell nuclei is essential for computational pathology, yet gigapixel Whole-Slide Images pose major computational challenges. Existing approaches rely on patch-based processing and costly post-processing for instance separation, sacrificing context and efficiency. We introduce LSP-DETR (Local Star Polygon DEtection TRansformer), a fully end-to-end framework that uses a lightweight transformer with linear complexity to process substantially larger images without additional computational cost. Nuclei are represented as star-convex polygons, and a novel radial distance loss function allows the segmentation of overlapping nuclei to emerge naturally, without requiring explicit overlap annotations or handcrafted post-processing. Evaluations on PanNuke and MoNuSeg show strong generalization across tissues and state-of-the-art efficiency, with LSP-DETR being over five times faster than the next-fastest leading method. Code and models are available at https://github.com/RationAI/lsp-detr.

The neurons of artificial neural networks were originally invented when much less was known about biological neurons than is known today. Our work explores a modification to the core neuron unit to make it more parallel to a biological neuron. The modification is made with the knowledge that biological dendrites are not simply passive activation funnels, but also compute complex non-linear functions as they transmit activation to the cell body. The paper explores a novel system of "Perforated" backpropagation empowering the artificial neurons of deep neural networks to achieve better performance coding for the same features they coded for in the original architecture. After an initial network training phase, additional "Dendrite Nodes" are added to the network and separately trained with a different objective: to correlate their output with the remaining error of the original neurons. The trained Dendrite Nodes are then frozen, and the original neurons are further trained, now taking into account the additional error signals provided by the Dendrite Nodes. The cycle of training the original neurons and then adding and training Dendrite Nodes can be repeated several times until satisfactory performance is achieved. Our algorithm was successfully added to modern state-of-the-art PyTorch networks across multiple domains, improving upon original accuracies and allowing for significant model compression without a loss in accuracy.

Most recently, there has been significant interest in learning contextual representations for various NLP tasks, by leveraging large scale text corpora to train large neural language models with self-supervised learning objectives, such as Masked Language Model (MLM). However, based on a pilot study, we observe three issues of existing general-purpose language models when they are applied to text-to-SQL semantic parsers: fail to detect column mentions in the utterances, fail to infer column mentions from cell values, and fail to compose complex SQL queries. To mitigate these issues, we present a model pre-training framework, Generation-Augmented Pre-training (GAP), that jointly learns representations of natural language utterances and table schemas by leveraging generation models to generate pre-train data. GAP MODEL is trained on 2M utterance-schema pairs and 30K utterance-schema-SQL triples, whose utterances are produced by generative models. Based on experimental results, neural semantic parsers that leverage GAP MODEL as a representation encoder obtain new state-of-the-art results on both SPIDER and CRITERIA-TO-SQL benchmarks.

Digital hematopathology requires cell-level analysis across diverse disease categories, including malignant disorders (e.g., leukemia), infectious conditions (e.g., malaria), and non-malignant red blood cell disorders (e.g., sickle cell disease). Whether single-task, vision-language, WSI-optimized, or single-cell hematology models, these approaches share a key limitation, they cannot provide unified, multi-task, multi-modal reasoning across the complexities of digital hematopathology. To overcome these limitations, we propose Uni-Hema, a multi-task, unified model for digital hematopathology integrating detection, classification, segmentation, morphology prediction, and reasoning across multiple diseases. Uni-Hema leverages 46 publicly available datasets, encompassing over 700K images and 21K question-answer pairs, and is built upon Hema-Former, a multimodal module that bridges visual and textual representations at the hierarchy level for the different tasks (detection, classification, segmentation, morphology, mask language modeling and visual question answer) at different granularity. Extensive experiments demonstrate that Uni-Hema achieves comparable or superior performance to train on a single-task and single dataset models, across diverse hematological tasks, while providing interpretable, morphologically relevant insights at the single-cell level. Our framework establishes a new standard for multi-task and multi-modal digital hematopathology. The code will be made publicly available.

The cell is arguably the most fundamental unit of life and is central to understanding biology. Accurate modeling of cells is important for this understanding as well as for determining the root causes of disease. Recent advances in artificial intelligence (AI), combined with the ability to generate large-scale experimental data, present novel opportunities to model cells. Here we propose a vision of leveraging advances in AI to construct virtual cells, high-fidelity simulations of cells and cellular systems under different conditions that are directly learned from biological data across measurements and scales. We discuss desired capabilities of such AI Virtual Cells, including generating universal representations of biological entities across scales, and facilitating interpretable in silico experiments to predict and understand their behavior using virtual instruments. We further address the challenges, opportunities and requirements to realize this vision including data needs, evaluation strategies, and community standards and engagement to ensure biological accuracy and broad utility. We envision a future where AI Virtual Cells help identify new drug targets, predict cellular responses to perturbations, as well as scale hypothesis exploration. With open science collaborations across the biomedical ecosystem that includes academia, philanthropy, and the biopharma and AI industries, a comprehensive predictive understanding of cell mechanisms and interactions has come into reach.

Cell identity encompasses various semantic aspects of a cell, including cell type, pathway information, disease information, and more, which are essential for biologists to gain insights into its biological characteristics. Understanding cell identity from the transcriptomic data, such as annotating cell types, has become an important task in bioinformatics. As these semantic aspects are determined by human experts, it is impossible for AI models to effectively carry out cell identity understanding tasks without the supervision signals provided by single-cell and label pairs. The single-cell pre-trained language models (PLMs) currently used for this task are trained only on a single modality, transcriptomics data, lack an understanding of cell identity knowledge. As a result, they have to be fine-tuned for downstream tasks and struggle when lacking labeled data with the desired semantic labels. To address this issue, we propose an innovative solution by constructing a unified representation of single-cell data and natural language during the pre-training phase, allowing the model to directly incorporate insights related to cell identity. More specifically, we introduce LangCell, the first Language-Cell pre-training framework. LangCell utilizes texts enriched with cell identity information to gain a profound comprehension of cross-modal knowledge. Results from experiments conducted on different benchmarks show that LangCell is the only single-cell PLM that can work effectively in zero-shot cell identity understanding scenarios, and also significantly outperforms existing models in few-shot and fine-tuning cell identity understanding scenarios.

Cells that collide with each other repolarize away from contact, in a process called contact inhibition of locomotion (CIL), which is necessary for correct development of the embryo. CIL can occur even when cells make a micron-scale contact with a neighbor - much smaller than their size. How precisely can a cell sense cell-cell contact and repolarize in the correct direction? What factors control whether a cell recognizes it has contacted a neighbor? We propose a theoretical model for the limits of CIL where cells recognize the presence of another cell by binding the protein ephrin with the Eph receptor. This recognition is made difficult by the presence of interfering ligands that bind nonspecifically. Both theoretical predictions and simulation results show that it becomes more difficult to sense cell-cell contact when it is difficult to distinguish ephrin from the interfering ligands, or when there are more interfering ligands, or when the contact width decreases. However, the error of estimating contact position remains almost constant when the contact width changes. This happens because the cell gains spatial information largely from the boundaries of cell-cell contact. We study using statistical decision theory the likelihood of a false positive CIL event in the absence of cell-cell contact, and the likelihood of a false negative where CIL does not occur when another cell is present. Our results suggest that the cell is more likely to make incorrect decisions when the contact width is very small or so large that it nears the cell's perimeter. However, in general, we find that cells have the ability to make reasonably reliable CIL decisions even for very narrow (micron-scale) contacts, even if the concentration of interfering ligands is ten times that of the correct ligands.

Drug discovery is fundamentally a process of inferring the effects of treatments on patients, and would therefore benefit immensely from computational models that can reliably simulate patient responses, enabling researchers to generate and test large numbers of therapeutic hypotheses safely and economically before initiating costly clinical trials. Even a more specific model that predicts the functional response of cells to a wide range of perturbations would be tremendously valuable for discovering safe and effective treatments that successfully translate to the clinic. Creating such virtual cells has long been a goal of the computational research community that unfortunately remains unachieved given the daunting complexity and scale of cellular biology. Nevertheless, recent advances in AI, computing power, lab automation, and high-throughput cellular profiling provide new opportunities for reaching this goal. In this perspective, we present a vision for developing and evaluating virtual cells that builds on our experience at Recursion. We argue that in order to be a useful tool to discover novel biology, virtual cells must accurately predict the functional response of a cell to perturbations and explain how the predicted response is a consequence of modifications to key biomolecular interactions. We then introduce key principles for designing therapeutically-relevant virtual cells, describe a lab-in-the-loop approach for generating novel insights with them, and advocate for biologically-grounded benchmarks to guide virtual cell development. Finally, we make the case that our approach to virtual cells provides a useful framework for building other models at higher levels of organization, including virtual patients. We hope that these directions prove useful to the research community in developing virtual models optimized for positive impact on drug discovery outcomes.

As Large Language Models (LLMs) rapidly evolve, their influence in science is becoming increasingly prominent. The emerging capabilities of LLMs in task generalization and free-form dialogue can significantly advance fields like chemistry and biology. However, the field of single-cell biology, which forms the foundational building blocks of living organisms, still faces several challenges. High knowledge barriers and limited scalability in current methods restrict the full exploitation of LLMs in mastering single-cell data, impeding direct accessibility and rapid iteration. To this end, we introduce ChatCell, which signifies a paradigm shift by facilitating single-cell analysis with natural language. Leveraging vocabulary adaptation and unified sequence generation, ChatCell has acquired profound expertise in single-cell biology and the capability to accommodate a diverse range of analysis tasks. Extensive experiments further demonstrate ChatCell's robust performance and potential to deepen single-cell insights, paving the way for more accessible and intuitive exploration in this pivotal field. Our project homepage is available at https://zjunlp.github.io/project/ChatCell.

High-content screening (HCS) assays based on high-throughput microscopy techniques such as Cell Painting have enabled the interrogation of cells' morphological responses to perturbations at an unprecedented scale. The collection of such data promises to facilitate a better understanding of the relationships between different perturbations and their effects on cellular state. Towards achieving this goal, recent advances in cross-modal contrastive learning could, in theory, be leveraged to learn a unified latent space that aligns perturbations with their corresponding morphological effects. However, the application of such methods to HCS data is not straightforward due to substantial differences in the semantics of Cell Painting images compared to natural images, and the difficulty of representing different classes of perturbations (e.g., small molecule vs CRISPR gene knockout) in a single latent space. In response to these challenges, here we introduce CellCLIP, a cross-modal contrastive learning framework for HCS data. CellCLIP leverages pre-trained image encoders coupled with a novel channel encoding scheme to better capture relationships between different microscopy channels in image embeddings, along with natural language encoders for representing perturbations. Our framework outperforms current open-source models, demonstrating the best performance in both cross-modal retrieval and biologically meaningful downstream tasks while also achieving significant reductions in computation time.

We present a general computational theory of cancer and its developmental dynamics. The theory is based on a theory of the architecture and function of developmental control networks which guide the formation of multicellular organisms. Cancer networks are special cases of developmental control networks. Cancer results from transformations of normal developmental networks. Our theory generates a natural classification of all possible cancers based on their network architecture. Each cancer network has a unique topology and semantics and developmental dynamics that result in distinct clinical tumor phenotypes. We apply this new theory with a series of proof of concept cases for all the basic cancer types. These cases have been computationally modeled, their behavior simulated and mathematically described using a multicellular systems biology approach. There are fascinating correspondences between the dynamic developmental phenotype of computationally modeled {\em in silico} cancers and natural {\em in vivo} cancers. The theory lays the foundation for a new research paradigm for understanding and investigating cancer. The theory of cancer networks implies that new diagnostic methods and new treatments to cure cancer will become possible.

Cell painting is a popular technique for creating human-interpretable, high-contrast images of cell morphology. There are two major issues with cell paint: (1) it is labor-intensive and (2) it requires chemical fixation, making the study of cell dynamics impossible. We train a diffusion model (Morphological Observation Neural Enhancement Tool, or MONET) on a large dataset to predict cell paint channels from brightfield images. We show that model quality improves with scale. The model uses a consistency architecture to generate time-lapse videos, despite the impossibility of obtaining cell paint video training data. In addition, we show that this architecture enables a form of in-context learning, allowing the model to partially transfer to out-of-distribution cell lines and imaging protocols. Virtual cell painting is not intended to replace physical cell painting completely, but to act as a complementary tool enabling novel workflows in biological research.

The Human Cell Atlas (HCA) will be made up of comprehensive reference maps of all human cells - the fundamental units of life - as a basis for understanding fundamental human biological processes and diagnosing, monitoring, and treating disease. It will help scientists understand how genetic variants impact disease risk, define drug toxicities, discover better therapies, and advance regenerative medicine. A resource of such ambition and scale should be built in stages, increasing in size, breadth, and resolution as technologies develop and understanding deepens. We will therefore pursue Phase 1 as a suite of flagship projects in key tissues, systems, and organs. We will bring together experts in biology, medicine, genomics, technology development and computation (including data analysis, software engineering, and visualization). We will also need standardized experimental and computational methods that will allow us to compare diverse cell and tissue types - and samples across human communities - in consistent ways, ensuring that the resulting resource is truly global. This document, the first version of the HCA White Paper, was written by experts in the field with feedback and suggestions from the HCA community, gathered during recent international meetings. The White Paper, released at the close of this yearlong planning process, will be a living document that evolves as the HCA community provides additional feedback, as technological and computational advances are made, and as lessons are learned during the construction of the atlas.

To understand the function of cortical circuits it is necessary to classify their underlying cellular diversity. Traditional attempts based on comparing anatomical or physiological features of neurons and glia, while productive, have not resulted in a unified taxonomy of neural cell types. The recent development of single-cell transcriptomics has enabled, for the first time, systematic high-throughput profiling of large numbers of cortical cells and the generation of datasets that hold the promise of being complete, accurate and permanent. Statistical analyses of these data have revealed the existence of clear clusters, many of which correspond to cell types defined by traditional criteria, and which are conserved across cortical areas and species. To capitalize on these innovations and advance the field, we, the Copenhagen Convention Group, propose the community adopts a transcriptome-based taxonomy of the cell types in the adult mammalian neocortex. This core classification should be ontological, hierarchical and use a standardized nomenclature. It should be configured to flexibly incorporate new data from multiple approaches, developmental stages and a growing number of species, enabling improvement and revision of the classification. This community-based strategy could serve as a common foundation for future detailed analysis and reverse engineering of cortical circuits and serve as an example for cell type classification in other parts of the nervous system and other organs.

Cell instance segmentation in cytology images has significant importance for biology analysis and cancer screening, while remains challenging due to 1) the extensive overlapping translucent cell clusters that cause the ambiguous boundaries, and 2) the confusion of mimics and debris as nuclei. In this work, we proposed a De-overlapping Network (DoNet) in a decompose-and-recombined strategy. A Dual-path Region Segmentation Module (DRM) explicitly decomposes the cell clusters into intersection and complement regions, followed by a Semantic Consistency-guided Recombination Module (CRM) for integration. To further introduce the containment relationship of the nucleus in the cytoplasm, we design a Mask-guided Region Proposal Strategy (MRP) that integrates the cell attention maps for inner-cell instance prediction. We validate the proposed approach on ISBI2014 and CPS datasets. Experiments show that our proposed DoNet significantly outperforms other state-of-the-art (SOTA) cell instance segmentation methods. The code is available at https://github.com/DeepDoNet/DoNet.

During developmental processes such as embryogenesis, how a group of cells fold into specific structures, is a central question in biology that defines how living organisms form. Establishing tissue-level morphology critically relies on how every single cell decides to position itself relative to its neighboring cells. Despite its importance, it remains a major challenge to understand and predict the behavior of every cell within the living tissue over time during such intricate processes. To tackle this question, we propose a geometric deep learning model that can predict multicellular folding and embryogenesis, accurately capturing the highly convoluted spatial interactions among cells. We demonstrate that multicellular data can be represented with both granular and foam-like physical pictures through a unified graph data structure, considering both cellular interactions and cell junction networks. We successfully use our model to achieve two important tasks, interpretable 4-D morphological sequence alignment, and predicting local cell rearrangements before they occur at single-cell resolution. Furthermore, using an activation map and ablation studies, we demonstrate that cell geometries and cell junction networks together regulate local cell rearrangement which is critical for embryo morphogenesis. This approach provides a novel paradigm to study morphogenesis, highlighting a unified data structure and harnessing the power of geometric deep learning to accurately model the mechanisms and behaviors of cells during development. It offers a pathway toward creating a unified dynamic morphological atlas for a variety of developmental processes such as embryogenesis.

There is a widening recognition that cancer cells are products of complex developmental processes. Carcinogenesis and metastasis formation are increasingly described as systems-level, network phenomena. Here we propose that malignant transformation is a two-phase process, where an initial increase of system plasticity is followed by a decrease of plasticity at late stages of carcinogenesis as a model of cellular learning. We describe the hallmarks of increased system plasticity of early, tumor initiating cells, such as increased noise, entropy, conformational and phenotypic plasticity, physical deformability, cell heterogeneity and network rearrangements. Finally, we argue that the large structural changes of molecular networks during cancer development necessitate a rather different targeting strategy in early and late phase of carcinogenesis. Plastic networks of early phase cancer development need a central hit, while rigid networks of late stage primary tumors or established metastases should be attacked by the network influence strategy, such as by edgetic, multi-target, or allo-network drugs. Cancer stem cells need special diagnosis and targeting, since their dormant and rapidly proliferating forms may have more rigid, or more plastic networks, respectively. The extremely high ability to change their rigidity/plasticity may be a key differentiating hallmark of cancer stem cells. The application of early stage-optimized anti-cancer drugs to late-stage patients may be a reason of many failures in anti-cancer therapies. Our hypotheses presented here underlie the need for patient-specific multi-target therapies applying the correct ratio of central hits and network influences -- in an optimized sequence.

The challenge of translating vast, multimodal biological data into predictive and mechanistic understanding of cellular function is a central theme in modern biology. Virtual cells, or digital cellular twins, have emerged as a critical paradigm to meet this challenge by creating integrative computational models of cellular processes. This review synthesizes the evolution and current state of the virtual cell, from foundational mechanistic frameworks like the Virtual Cell that employ deterministic and stochastic simulations to the recent transformative impact of artificial intelligence and foundation models. We examine the core technological pillars required to build these models, including the integration of various data types, such as single-cell and spatial omics, the spectrum of modeling approaches, and the bioengineering principles that connect simulation to application. We further discuss key applications, frameworks for model benchmarking and validation, and the significant hurdles that remain, including computational scalability, parameter inference, and ethical considerations, which provides a roadmap for development of predictive virtual cells that promise to revolutionize biomedical research and clinical practice.

Single-cell CRISPR screens summarize each perturbation by how far cells move from their unperturbed state, averaging over cell-to-cell variation. Whether the cells moved together is not captured: two perturbations with identical effect magnitude can differ qualitatively, one driving cells along a shared trajectory, the other scattering them around the same mean. We define SheshaP coherence (S_p), the mean cosine similarity between individual cell displacement vectors and their mean, and ask what it adds across six Perturb-seq datasets (2,285 perturbations; CRISPRa, CRISPRi, Cas9 knockout). Coherence and effect magnitude are closely coupled (Spearman ρ=0.84--0.98), and the coupling persists in a foundation-model embedding, under alternative effect-size definitions, and when analysis is restricted to responding cells. Associations reported without conditioning on effect size largely recover it, shown here for two comparisons that vanish under conditioning. Effect size accounts for 89--96\% of coherence variance; within the remainder, coherence is negatively associated with apoptosis and p53 signalling in the two largest screens. Two standard responder classifiers agree on only 68\% of cells. Directional coherence is largely a restatement of effect magnitude, and heterogeneity measures should report their redundancy with effect size as a matter of course. S_p is implemented in the open-source shesha-geometry Python package.

Several ongoing international efforts are developing methods of localizing single cells within organs or mapping the entire human body at the single cell level, including the Chan Zuckerberg Initiative's Human Cell Atlas (HCA), and the Knut and Allice Wallenberg Foundation's Human Protein Atlas (HPA), and the National Institutes of Health's Human BioMolecular Atlas Program (HuBMAP). Their goals are to understand cell specialization, interactions, spatial organization in their natural context, and ultimately the function of every cell within the body. In the same way that the Human Genome Project had to assemble sequence data from different people to construct a complete sequence, multiple centers around the world are collecting tissue specimens from a diverse population that varies in age, race, sex, and body size. A challenge will be combining these heterogeneous tissue samples into a 3D reference map that will enable multiscale, multidimensional Google Maps-like exploration of the human body. Key to making alignment of tissue samples work is identifying and using a coordinate system called a Common Coordinate Framework (CCF), which defines the positions, or "addresses", in a reference body, from whole organs down to functional tissue units and individual cells. In this perspective, we examine the concept of a CCF based on the vasculature and describe why it would be an attractive choice for mapping the human body.

Many examples of cooperation exist in biology. In chemical systems however, which can sometimes be quite complex, we do not appear to observe intricate cooperative interactions. A key question for the origin of life, is then how can molecular cooperation first arise in an abiotic system prior to the emergence of biological replication. We postulate that selection at the molecular level is a driving force behind the complexification of chemical systems, particularly during the origins of life. In the theory of multilevel selection the two selective forces are: within-group and between-group, where the former tends to favor "selfish" replication of individuals and the latter favor cooperation between individuals enhancing the replication of the group as a whole. These forces can be quantified using the Price equation, which is a standard tool used in evolutionary biology to quantify evolutionary change. Our central claim is that replication and heredity in chemical systems are subject to selection, and quantifiable using the multilevel Price equation. We demonstrate this using the Graded Autocatalysis Replication Domain computer model, describing simple protocell composed out of molecules and its replication, which respectively analogue to the group and the individuals. In contrast to previous treatments of this model, we treat the lipid molecules themselves as replicating individuals and the protocells they form as groups of individuals. Our goal is to demonstrate how evolutionary biology tools and concepts can be applied in chemistry and we suggest that molecular cooperation may arise as a result of group selection. Further, the biological relation of parent-progeny is proposed to be analogue to the reactant-product relation in chemistry, thus allowing for tools from evolutionary biology to be applied to chemistry and would deepen the connection between chemistry and biology.

Large language models (LLMs) and emerging agentic frameworks are beginning to transform single-cell biology by enabling natural-language reasoning, generative annotation, and multimodal data integration. However, progress remains fragmented across data modalities, architectures, and evaluation standards. LLM4Cell presents the first unified survey of 58 foundation and agentic models developed for single-cell research, spanning RNA, ATAC, multi-omic, and spatial modalities. We categorize these methods into five families-foundation, text-bridge, spatial, multimodal, epigenomic, and agentic-and map them to eight key analytical tasks including annotation, trajectory and perturbation modeling, and drug-response prediction. Drawing on over 40 public datasets, we analyze benchmark suitability, data diversity, and ethical or scalability constraints, and evaluate models across 10 domain dimensions covering biological grounding, multi-omics alignment, fairness, privacy, and explainability. By linking datasets, models, and evaluation domains, LLM4Cell provides the first integrated view of language-driven single-cell intelligence and outlines open challenges in interpretability, standardization, and trustworthy model development.

Virtual cell modeling aims to predict cellular responses to perturbations. Existing virtual cell models rely heavily on large-scale single-cell datasets, learning explicit mappings between gene expression and perturbations. Although recent models attempt to incorporate multi-source biological information, their generalization remains constrained by data quality, coverage, and batch effects. More critically, these models often function as black boxes, offering predictions without interpretability or consistency with biological principles, which undermines their credibility in scientific research. To address these challenges, we present VCWorld, a cell-level white-box simulator that integrates structured biological knowledge with the iterative reasoning capabilities of large language models to instantiate a biological world model. VCWorld operates in a data-efficient manner to reproduce perturbation-induced signaling cascades and generates interpretable, stepwise predictions alongside explicit mechanistic hypotheses. In drug perturbation benchmarks, VCWorld achieves state-of-the-art predictive performance, and the inferred mechanistic pathways are consistent with publicly available biological evidence.

Large-scale cell microscopy screens are used in drug discovery and molecular biology research to study the effects of millions of chemical and genetic perturbations on cells. To use these images in downstream analysis, we need models that can map each image into a feature space that represents diverse biological phenotypes consistently, in the sense that perturbations with similar biological effects have similar representations. In this work, we present the largest foundation model for cell microscopy data to date, a new 1.9 billion-parameter ViT-G/8 MAE trained on over 8 billion microscopy image crops. Compared to a previous published ViT-L/8 MAE, our new model achieves a 60% improvement in linear separability of genetic perturbations and obtains the best overall performance on whole-genome biological relationship recall and replicate consistency benchmarks. Beyond scaling, we developed two key methods that improve performance: (1) training on a curated and diverse dataset; and, (2) using biologically motivated linear probing tasks to search across each transformer block for the best candidate representation of whole-genome screens. We find that many self-supervised vision transformers, pretrained on either natural or microscopy images, yield significantly more biologically meaningful representations of microscopy images in their intermediate blocks than in their typically used final blocks. More broadly, our approach and results provide insights toward a general strategy for successfully building foundation models for large-scale biological data.

Subcellular localization is a crucial biological task for drug target identification and function annotation. Although it has been biologically realized that subcellular localization is closely associated with protein structure, no existing dataset offers comprehensive 3D structural information with detailed subcellular localization annotations, thus severely hindering the application of promising structure-based models on this task. To address this gap, we introduce a new benchmark called CAPSUL, a Comprehensive humAn Protein benchmark for SUbcellular Localization. It features a dataset that integrates diverse 3D structural representations with fine-grained subcellular localization annotations carefully curated by domain experts. We evaluate this benchmark using a variety of state-of-the-art sequence-based and structure-based models, showcasing the importance of involving structural features in this task. Furthermore, we explore reweighting and single-label classification strategies to facilitate future investigation on structure-based methods for this task. Lastly, we showcase the powerful interpretability of structure-based methods through a case study on the Golgi apparatus, where we discover a decisive localization pattern α-helix from attention mechanisms, demonstrating the potential for bridging the gap with intuitive biological interpretability and paving the way for data-driven discoveries in cell biology.

Artificial Intelligence Virtual Cells (AIVCs) aim to learn executable, decision-relevant models of cell state from multimodal, multiscale measurements. Recent studies have introduced single-cell and spatial foundation models, improved cross-modality alignment, scaled perturbation atlases, and explored pathway-level readouts. Nevertheless, although held-out validation is standard practice, evaluations remain predominantly within single datasets and settings; evidence indicates that transport across laboratories and platforms is often limited, that some data splits are vulnerable to leakage and coverage bias, and that dose, time and combination effects are not yet systematically handled. Cross-scale coupling also remains constrained, as anchors linking molecular, cellular and tissue levels are sparse, and alignment to scientific or clinical readouts varies across studies. We propose a model-agnostic Cell-State Latent (CSL) perspective that organizes learning via an operator grammar: measurement, lift/project for cross-scale coupling, and intervention for dosing and scheduling. This view motivates a decision-aligned evaluation blueprint across modality, scale, context and intervention, and emphasizes function-space readouts such as pathway activity, spatial neighborhoods and clinically relevant endpoints. We recommend operator-aware data design, leakage-resistant partitions, and transparent calibration and reporting to enable reproducible, like-for-like comparisons.

Image-based or morphological profiling is a rapidly expanding field wherein cells are "profiled" by extracting hundreds to thousands of unbiased, quantitative features from images of cells that have been perturbed by genetic or chemical perturbations. The Cell Painting assay is the most popular imaged-based profiling assay wherein six small-molecule dyes label eight cellular compartments and thousands of measurements are made, describing quantitative traits such as size, shape, intensity, and texture within the nucleus, cytoplasm, and whole cell (Cimini et al., 2023). We have created the Cell Painting Gallery, a publicly available collection of Cell Painting datasets, with granular dataset descriptions and access instructions. It is hosted by AWS on the Registry of Open Data (RODA). As of January 2024, the Cell Painting Gallery holds 656 terabytes (TB) of image and associated numerical data. It includes the largest publicly available Cell Painting dataset, in terms of perturbations tested (Joint Undertaking for Morphological Profiling or JUMP (Chandrasekaran et al., 2023)), along with many other canonical datasets using Cell Painting, close derivatives of Cell Painting (such as LipocyteProfiler (Laber et al., 2023) and Pooled Cell Painting (Ramezani et al., 2023)).

Cell type annotation is a key task in analyzing the heterogeneity of single-cell RNA sequencing data. Although recent foundation models automate this process, they typically annotate cells independently, without considering batch-level cellular context or providing explanatory reasoning. In contrast, human experts often annotate distinct cell types for different cell clusters based on their domain knowledge. To mimic this workflow, we introduce the CellPuzzles task, where the objective is to assign unique cell types to a batch of cells. This benchmark spans diverse tissues, diseases, and donor conditions, and requires reasoning across the batch-level cellular context to ensure label uniqueness. We find that off-the-shelf large language models (LLMs) struggle on CellPuzzles, with the best baseline (OpenAI's o1) achieving only 19.0% batch-level accuracy. To fill this gap, we propose Cell-o1, a 7B LLM trained via supervised fine-tuning on distilled reasoning traces, followed by reinforcement learning with batch-level rewards. Cell-o1 achieves state-of-the-art performance, outperforming o1 by over 73% and generalizing well across contexts. Further analysis of training dynamics and reasoning behaviors provides insights into batch-level annotation performance and emergent expert-like reasoning. Code and data are available at https://github.com/ncbi-nlp/cell-o1.

The advent of single-cell technology has significantly improved our understanding of cellular states and subpopulations in various tissues under normal and diseased conditions by employing data-driven approaches such as clustering and trajectory inference. However, these methods consider cells as independent data points of population distributions. With spatial transcriptomics, we can represent cellular organization, along with dynamic cell-cell interactions that lead to changes in cell state. Still, key computational advances are necessary to enable the data-driven learning of such complex interactive cellular dynamics. While agent-based modeling (ABM) provides a powerful framework, traditional approaches rely on handcrafted rules derived from domain knowledge rather than data-driven approaches. To address this, we introduce Spatio Temporal Agent-Based Graph Evolution Dynamics(STAGED) integrating ABM with deep learning to model intercellular communication, and its effect on the intracellular gene regulatory network. Using graph ODE networks (GDEs) with shared weights per cell type, our approach represents genes as vertices and interactions as directed edges, dynamically learning their strengths through a designed attention mechanism. Trained to match continuous trajectories of simulated as well as inferred trajectories from spatial transcriptomics data, the model captures both intercellular and intracellular interactions, enabling a more adaptive and accurate representation of cellular dynamics.

The structure-function relationship is at the heart of biology and major protein deformations are correlated to specific functions. In the case of heme proteins, doming is associated with the respiratory function in hemoglobin and myoglobin, while ruffling has been correlated with electron transfer processes, such as in the case of Cytochrome c (Cyt c). The latter has indeed evolved to become an important electron transfer protein in humans. In its ferrous form, it undergoes ligand release and doming upon photoexcitation, but its ferric form does not release the distal ligand, while the return to the ground state has been attributed to thermal relaxation. Here, by combining femtosecond Fe K-edge X-ray absorption near-edge structure (XANES) studies and femtosecond Fe Kalpha and Kbeta X-ray emission spectroscopy (XES), we demonstrate that the photocycle of ferric Cyt c is entirely due to a cascade among excited spin states of the Iron ion, causing the ferric heme to undergo doming, which we identify for the first time. We also argue that this pattern is common to all ferric haems, raising the question of the biological relevance of doming in such proteins.

Within the complex neuroarchitecture of the brain, astrocytes play crucial roles in development, structure, and metabolism. These cells regulate neural activity through tripartite synapses, directly impacting cognitive processes such as learning and memory. Despite the growing recognition of astrocytes' significance, traditional Spiking Neural Network (SNN) models remain predominantly neuron-centric, overlooking the profound influence of astrocytes on neural dynamics. Inspired by these biological insights, we have developed an Astrocyte-Modulated Spiking Unit (AM-SU), an innovative framework that integrates neuron-astrocyte interactions into the computational paradigm, demonstrating wide applicability across various hardware platforms. Our Astrocyte-Modulated Spiking Neural Network (AstroSNN) exhibits exceptional performance in tasks involving memory retention and natural language generation, particularly in handling long-term dependencies and complex linguistic structures. The design of AstroSNN not only enhances its biological authenticity but also introduces novel computational dynamics, enabling more effective processing of complex temporal dependencies. Furthermore, AstroSNN shows low latency, high throughput, and reduced memory usage in practical applications, making it highly suitable for resource-constrained environments. By successfully integrating astrocytic dynamics into intelligent neural networks, our work narrows the gap between biological plausibility and neural modeling, laying the groundwork for future biologically-inspired neural computing research that includes both neurons and astrocytes.

Instance segmentation of overlapping cells in microscopy remains challenging due to semi-transparent structures that produce weak boundaries and mixed visual evidence in overlap regions. Existing methods address this through local regions of interest or shape priors but lack global reasoning across overlapping objects. We present QCell, a novel query-based model that de-overlaps cell instances in microscopy scenes. Our approach combines (i) an instance recombination module that decomposes and recombines query representations in latent space, enabling the model to reason about complete object structure under overlap, and (ii) a contrastive query alignment objective that combines distinctive instance feature learning and separation of overlapping cell queries. We additionally introduce a new Organoid dataset benchmark for overlapping cell segmentation. We show that QCell outperforms state-of-the-art methods across multiple benchmarks, achieving +2.2 AP and +2.7 AJI on ISBI2014. Code is available at https://github.com/SlavkoPrytula/QCell

Recent advancements in single-cell multi-omics, particularly RNA-seq, have provided profound insights into cellular heterogeneity and gene regulation. While pre-trained language model (PLM) paradigm based single-cell foundation models have shown promise, they remain constrained by insufficient integration of in-depth individual profiles and neglecting the influence of noise within multi-modal data. To address both issues, we propose an Open-world Language Knowledge-Aided Robust Single-Cell Foundation Model (OKR-CELL). It is built based on a cross-modal Cell-Language pre-training framework, which comprises two key innovations: (1) leveraging Large Language Models (LLMs) based workflow with retrieval-augmented generation (RAG) enriches cell textual descriptions using open-world knowledge; (2) devising a Cross-modal Robust Alignment (CRA) objective that incorporates sample reliability assessment, curriculum learning, and coupled momentum contrastive learning to strengthen the model's resistance to noisy data. After pretraining on 32M cell-text pairs, OKR-CELL obtains cutting-edge results across 6 evaluation tasks. Beyond standard benchmarks such as cell clustering, cell-type annotation, batch-effect correction, and few-shot annotation, the model also demonstrates superior performance in broader multi-modal applications, including zero-shot cell-type annotation and bidirectional cell-text retrieval.

High-content cellular imaging, transcriptomics, and proteomics data provide rich and complementary views on the molecular layers of biology that influence cellular states and function. However, the biological determinants through which changes in multi-omics measurements influence cellular morphology have not yet been systematically explored, and the degree to which cell imaging could potentially enable the prediction of multi-omics directly from cell imaging data is therefore currently unclear. Here, we address the question of whether it is possible to predict bulk multi-omics measurements directly from cell images using Image2Omics - a deep learning approach that predicts multi-omics in a cell population directly from high-content images of cells stained with multiplexed fluorescent dyes. We perform an experimental evaluation in gene-edited macrophages derived from human induced pluripotent stem cells (hiPSC) under multiple stimulation conditions and demonstrate that Image2Omics achieves significantly better performance in predicting transcriptomics and proteomics measurements directly from cell images than predictions based on the mean observed training set abundance. We observed significant predictability of abundances for 4927 (18.72%; 95% CI: 6.52%, 35.52%) and 3521 (13.38%; 95% CI: 4.10%, 32.21%) transcripts out of 26137 in M1 and M2-stimulated macrophages respectively and for 422 (8.46%; 95% CI: 0.58%, 25.83%) and 697 (13.98%; 95% CI: 2.41%, 32.83%) proteins out of 4986 in M1 and M2-stimulated macrophages respectively. Our results show that some transcript and protein abundances are predictable from cell imaging and that cell imaging may potentially, in some settings and depending on the mechanisms of interest and desired performance threshold, even be a scalable and resource-efficient substitute for multi-omics measurements.

Understanding cellular mechanisms requires integrating information across DNA, RNA, and protein - the three molecular systems linked by the Central Dogma of molecular biology. While domain-specific foundation models have achieved success for each modality individually, they remain isolated, limiting our ability to model integrated cellular processes. Here we present the Central Dogma Transformer (CDT), an architecture that integrates pre-trained language models for DNA, RNA, and protein following the directional logic of the Central Dogma. CDT employs directional cross-attention mechanisms - DNA-to-RNA attention models transcriptional regulation, while RNA-to-Protein attention models translational relationships - producing a unified Virtual Cell Embedding that integrates all three modalities. We validate CDT v1 - a proof-of-concept implementation using fixed (non-cell-specific) RNA and protein embeddings - on CRISPRi enhancer perturbation data from K562 cells, achieving a Pearson correlation of 0.503, representing 63% of the theoretical ceiling set by cross-experiment variability (r = 0.797). Attention and gradient analyses provide complementary interpretive windows: in detailed case studies, these approaches highlight largely distinct genomic regions, with gradient analysis identifying a CTCF binding site that Hi-C data showed as physically contacting both enhancer and target gene. These results suggest that AI architectures aligned with biological information flow can achieve both predictive accuracy and mechanistic interpretability.

Complex gene interactions play a significant role in cancer progression, driving cellular behaviors that contribute to tumor growth, invasion, and metastasis. Gene co-expression networks model the functional connectivity between genes under various biological conditions. Understanding the system-level evolution of these networks in cancer is critical for elucidating disease mechanisms and informing the development of targeted therapies. While previous studies have primarily focused on structural differences between cancer and normal cell co-expression networks, this study applies graph frequency analysis to cancer transcriptomic signals defined on gene co-expression networks, highlighting the graph spectral characteristics of cancer systems. Using a range of graph frequency filters, we showed that cancer cells display distinctive patterns in the graph frequency content of their gene transcriptomic signals, effectively distinguishing between cancer types and stages. The transformation of the original gene feature space into the graph spectral space captured more intricate cancer properties, as validated by significantly higher F-statistic scores for graph frequency-filtered gene features compared to those in the original space.

Segmenting cells and tracking their motion over time is a common task in biomedical applications. However, predicting accurate instance-wise segmentation and cell motions from microscopy imagery remains a challenging task. Using microstructured environments for analyzing single cells in a constant flow of media adds additional complexity. While large-scale labeled microscopy datasets are available, we are not aware of any large-scale dataset, including both cells and microstructures. In this paper, we introduce the trapped yeast cell (TYC) dataset, a novel dataset for understanding instance-level semantics and motions of cells in microstructures. We release 105 dense annotated high-resolution brightfield microscopy images, including about 19k instance masks. We also release 261 curated video clips composed of 1293 high-resolution microscopy images to facilitate unsupervised understanding of cell motions and morphology. TYC offers ten times more instance annotations than the previously largest dataset, including cells and microstructures. Our effort also exceeds previous attempts in terms of microstructure variability, resolution, complexity, and capturing device (microscopy) variability. We facilitate a unified comparison on our novel dataset by introducing a standardized evaluation strategy. TYC and evaluation code are publicly available under CC BY 4.0 license.

Single-cell perturbation studies face dual heterogeneity bottlenecks: (i) semantic heterogeneity--identical biological concepts encoded under incompatible metadata schemas across datasets; and (ii) statistical heterogeneity--distribution shifts from biological variation demanding dataset-specific inductive biases. We propose HarmonyCell, an end-to-end agent framework resolving each challenge through a dedicated mechanism: an LLM-driven Semantic Unifier autonomously maps disparate metadata into a canonical interface without manual intervention; and an adaptive Monte Carlo Tree Search engine operates over a hierarchical action space to synthesize architectures with optimal statistical inductive biases for distribution shifts. Evaluated across diverse perturbation tasks under both semantic and distribution shifts, HarmonyCell achieves a 95% valid execution rate on heterogeneous input datasets (versus 0% for general agents) while matching or even exceeding expert-designed baselines in rigorous out-of-distribution evaluations. This dual-track orchestration enables scalable automatic virtual cell modeling without dataset-specific engineering.

We present an approach of using AI to model and simulate biology and life. Why is it important? Because at the core of medicine, pharmacy, public health, longevity, agriculture and food security, environmental protection, and clean energy, it is biology at work. Biology in the physical world is too complex to manipulate and always expensive and risky to tamper with. In this perspective, we layout an engineering viable approach to address this challenge by constructing an AI-Driven Digital Organism (AIDO), a system of integrated multiscale foundation models, in a modular, connectable, and holistic fashion to reflect biological scales, connectedness, and complexities. An AIDO opens up a safe, affordable and high-throughput alternative platform for predicting, simulating and programming biology at all levels from molecules to cells to individuals. We envision that an AIDO is poised to trigger a new wave of better-guided wet-lab experimentation and better-informed first-principle reasoning, which can eventually help us better decode and improve life.

The cell cortex and cell adhesion contribute to the mechanics of epithelial cells and hence tissues. Vertex models of epithelia represent the cell cortex and cell adhesion, but these models mostly ignore the other subcellular structures that compose the cytoplasm surrounded by the cortex. Here, we reveal the mechanical consequences of these structures in a minimal vertex model of an epithelial monolayer, in which the single-cell energy includes a cytoplasmic contribution that represents, e.g., the cost of confinement of cytosolic polymers. Strikingly, our simulations show that the buckling transition of the monolayer under compression becomes discontinuous in an intermediate range of values of the associated cytoplasmic modulus. By asymptotic solution of this buckling problem in the continuum limit of the model, we explain this reentrant behaviour in terms of the tricritical points of a sixth-order Landau theory. Our results thus underline how cell-scale mechanics beyond the cortex and cell adhesion can change emergent, tissue-scale behaviour even qualitatively.

We report DynaCLR, a self-supervised method for embedding cell and organelle Dynamics via Contrastive Learning of Representations of time-lapse images. DynaCLR integrates single-cell tracking and time-aware contrastive sampling to learn robust, temporally regularized representations of cell dynamics. DynaCLR embeddings generalize effectively to in-distribution and out-of-distribution datasets, and can be used for several downstream tasks with sparse human annotations. We demonstrate efficient annotations of cell states with a human-in-the-loop using fluorescence and label-free imaging channels. DynaCLR method enables diverse downstream biological analyses: classification of cell division and infection, clustering heterogeneous cell migration patterns, cross-modal distillation of cell states from fluorescence to label-free channel, alignment of asynchronous cellular responses and broken cell tracks, and discovering organelle response due to infection. DynaCLR is a flexible method for comparative analyses of dynamic cellular responses to pharmacological, microbial, and genetic perturbations. We provide PyTorch-based implementations of the model training and inference pipeline (https://github.com/mehta-lab/viscy) and a GUI (https://github.com/czbiohub-sf/napari-iohub) for the visualization and annotation of trajectories of cells in the real space and the embedding space.

Single-cell foundation models learn by reconstructing masked gene expression, implicitly treating technical noise as signal. With dropout rates exceeding 90%, reconstruction objectives encourage models to encode measurement artifacts rather than stable cellular programs. We introduce Cell-JEPA, a joint-embedding predictive architecture that shifts learning from reconstructing sparse counts to predicting in latent space. The key insight is that cell identity is redundantly encoded across genes. We show predicting cell-level embeddings from partial observations forces the model to learn dropout-robust features. On cell-type clustering, Cell-JEPA achieves 0.72 AvgBIO in zero-shot transfer versus 0.53 for scGPT, a 36% relative improvement. On perturbation prediction within a single cell line, Cell-JEPA improves absolute-state reconstruction but not effect-size estimation, suggesting that representation learning and perturbation modeling address complementary aspects of cellular prediction.

Understanding the biological mechanism of disease is critical for medicine, and in particular drug discovery. AI-powered analysis of genome-scale biological data hold great potential in this regard. The increasing availability of single-cell RNA sequencing data has enabled the development of large foundation models for disease biology. However, existing foundation models either do not improve or only modestly improve over task-specific models in downstream applications. Here, we explored two avenues for improving the state-of-the-art. First, we scaled the pre-training dataset to 116 million cells, which is larger than those used by previous models. Second, we leveraged the availability of large-scale biological annotations as a form of supervision during pre-training. We trained the TEDDY family of models comprising six transformer-based state-of-the-art single-cell foundation models with 70 million, 160 million, and 400 million parameters. We vetted our models on two downstream evaluation tasks -- identifying the underlying disease state of held-out donors not seen during training and distinguishing healthy cells from diseased ones for disease conditions and donors not seen during training. Scaling experiments showed that performance improved predictably with both data volume and parameter count. Our models showed substantial improvement over existing work on the first task and more muted improvements on the second.

Biological tissues exhibit complex behaviors with their dynamics often resembling inert soft matter such as liquids, polymers, colloids, and liquid crystals. These analogies enable physics-based approaches for investigations of emergent behaviors in biological processes. A well-studied case is the spreading of cellular aggregates on solid surfaces, where they display dynamics similar to viscous droplets. In vivo, however, cells and tissues are in a confined environment with varying geometries and mechanical properties to which they need to adapt. In this work, we compressed cellular aggregates between two solid surfaces and studied their dynamics using microscopy, and computer simulations. The confined cellular aggregates transitioned from compressed spheres into dynamic living capillary bridges exhibiting bridge thinning and a convex-to-concave meniscus curvature transition. We found that the stability of the bridge is determined by the interplay between cell growth and cell spreading on the confining surfaces. This interaction leads to bridge rupture at a critical length scale determined by the distance between the plates. The force distributions, formation and stability regimes of the living capillary bridges were characterized with full 3D computer simulations that included cell division, migration and growth dynamics, directly showing how mechanical principles govern the behavior of the living bridges; cellular aggregates display jamming and stiffening analogously to granular matter, and cell division along the long axis enhances thinning. Based on our results, we propose a new class of active soft matter behavior, where cellular aggregates exhibit liquid-like adaptation to confinement, but with self-organized rupturing driven by biological activity.

Background: Two strains of the endoparasitoid Cotesia typhae present a differential parasitism success on the host, Sesamia nonagrioides. One is virulent on both permissive and resistant host populations, and the other only on the permissive host. This interaction provides a very interesting frame for studying virulence factors. Here, we used a combination of comparative transcriptomic and proteomic analyses to unravel the molecular basis underlying virulence differences between the strains.Results: First, we report that virulence genes are mostly expressed during the nymphal stage of the parasitoid. Especially, proviral genes are broadly up-regulated at this stage, while their expression is only expected in the host. Parasitoid gene expression in the host increases with time, indicating the production of more virulence factors. Secondly, comparison between strains reveals differences in venom composition, with 12 proteins showing differential abundance. Proviral expression in the host displays a strong temporal variability, along with differential patterns between strains. Notably, a subset of proviral genes including protein-tyrosine phosphatases is specifically over-expressed in the resistant host parasitized by the less virulent strain, 24 hours after parasitism. This result particularly hints at host modulation of proviral expression.Conclusions: This study sheds light on the temporal expression of virulence factors of Cotesia typhae, both in the host and in the parasitoid. It also identifies potential molecular candidates driving differences in parasitism success between two strains. Together, those findings provide a path for further exploration of virulence mechanisms in parasitoid wasps, and offer insights into host-parasitoid coevolution.

Computational microscopy, in which hardware and algorithms of an imaging system are jointly designed, shows promise for making imaging systems that cost less, perform more robustly, and collect new types of information. Often, the performance of computational imaging systems, especially those that incorporate machine learning, is sample-dependent. Thus, standardized datasets are an essential tool for comparing the performance of different approaches. Here, we introduce the Berkeley Single Cell Computational Microscopy (BSCCM) dataset, which contains over ~12,000,000 images of 400,000 of individual white blood cells. The dataset contains images captured with multiple illumination patterns on an LED array microscope and fluorescent measurements of the abundance of surface proteins that mark different cell types. We hope this dataset will provide a valuable resource for the development and testing of new algorithms in computational microscopy and computer vision with practical biomedical applications.

Acute lymphoblastic leukemia (ALL) is a pervasive pediatric white blood cell cancer across the globe. With the popularity of convolutional neural networks (CNNs), computer-aided diagnosis of cancer has attracted considerable attention. Such tools are easily deployable and are cost-effective. Hence, these can enable extensive coverage of cancer diagnostic facilities. However, the development of such a tool for ALL cancer was challenging so far due to the non-availability of a large training dataset. The visual similarity between the malignant and normal cells adds to the complexity of the problem. This paper discusses the recent release of a large dataset and presents a novel deep learning architecture for the classification of cell images of ALL cancer. The proposed architecture, namely, SDCT-AuxNet^θ is a 2-module framework that utilizes a compact CNN as the main classifier in one module and a Kernel SVM as the auxiliary classifier in the other one. While CNN classifier uses features through bilinear-pooling, spectral-averaged features are used by the auxiliary classifier. Further, this CNN is trained on the stain deconvolved quantity images in the optical density domain instead of the conventional RGB images. A novel test strategy is proposed that exploits both the classifiers for decision making using the confidence scores of their predicted class labels. Elaborate experiments have been carried out on our recently released public dataset of 15114 images of ALL cancer and healthy cells to establish the validity of the proposed methodology that is also robust to subject-level variability. A weighted F1 score of 94.8% is obtained that is best so far on this challenging dataset.

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.

Breast Cancer is a major public health problem and the most common diagnosed malignancy in woman. There have been significant developments in clinical approaches and theoretical experimental to understand the interactions of cancer cells dynamics with the immune system, also developments on analytical and computational models to help provide insights into clinical observations for a better understanding of cancer cells, but more are needed, especially at the genetic and molecular levels mathematically. Treatments such as immunotherapy, chemotherapy, hormone therapy, radiotherapy, and gene therapy are the main strategies in the fight against breast cancer. The present study aims at investigating the effects of estrogen derived from recent models, but this time combined with immunotherapy as a way to treat or inhibit the cancer growth by a mathematical model of breast cancer in situ, governed by a simplified model of nonlinear-coupled ordinary differential equations, that combines important interactions between natural cells, tumor cells, immune cells, ketogenic diet in the presence of an anticancer drug. Another contribution was to introduce the inhibition effect epsilon for new results and conclusions, A qualitative study was performed and biological interpretations were included to understand the conditions of stability in a realistic way.

We algorithmically determine the regions and facets of all dimensions of the canonical polyhedral complex, the universal object into which a ReLU network decomposes its input space. We show that the locations of the vertices of the canonical polyhedral complex along with their signs with respect to layer maps determine the full facet structure across all dimensions. We present an algorithm which calculates this full combinatorial structure, making use of our theorems that the dual complex to the canonical polyhedral complex is cubical and it possesses a multiplication compatible with its facet structure. The resulting algorithm is numerically stable, polynomial time in the number of intermediate neurons, and obtains accurate information across all dimensions. This permits us to obtain, for example, the true topology of the decision boundaries of networks with low-dimensional inputs. We run empirics on such networks at initialization, finding that width alone does not increase observed topology, but width in the presence of depth does. Source code for our algorithms is accessible online at https://github.com/mmasden/canonicalpoly.

With the advent of novel cancer treatment options such as immunotherapy, studying the tumour immune micro-environment (TIME) is crucial to inform on prognosis and understand potential response to therapeutic agents. A key approach to characterising the TIME may be through combining (1) digitised microscopic high-resolution optical images of hematoxylin and eosin (H&E) stained tissue sections obtained in routine histopathology examinations with (2) automated immune cell detection and classification methods. In this work, we introduce a workflow to automatically generate robust single cell contours and labels from dually stained tissue sections with H&E and multiplexed immunofluorescence (IF) markers. The approach harnesses the Segment Anything Model and requires minimal human intervention compared to existing single cell databases. With this methodology, we create Immunocto, a massive, multi-million automatically generated database of 6,848,454 human cells and objects, including 2,282,818 immune cells distributed across 4 subtypes: CD4^+ T cell lymphocytes, CD8^+ T cell lymphocytes, CD20^+ B cell lymphocytes, and CD68^+/CD163^+ macrophages. For each cell, we provide a 64times64 pixels^2 H&E image at 40times magnification, along with a binary mask of the nucleus and a label. The database, which is made publicly available, can be used to train models to study the TIME on routine H&E slides. We show that deep learning models trained on Immunocto result in state-of-the-art performance for lymphocyte detection. The approach demonstrates the benefits of using matched H&E and IF data to generate robust databases for computational pathology applications.

Modern life sciences research is increasingly relying on artificial intelligence approaches to model biological systems, primarily centered around the use of machine learning (ML) models. Although ML is undeniably useful for identifying patterns in large, complex data sets, its widespread application in biological sciences represents a significant deviation from traditional methods of scientific inquiry. As such, the interplay between these models and scientific understanding in biology is a topic with important implications for the future of scientific research, yet it is a subject that has received little attention. Here, we draw from an epistemological toolkit to contextualize recent applications of ML in biological sciences under modern philosophical theories of understanding, identifying general principles that can guide the design and application of ML systems to model biological phenomena and advance scientific knowledge. We propose that conceptions of scientific understanding as information compression, qualitative intelligibility, and dependency relation modelling provide a useful framework for interpreting ML-mediated understanding of biological systems. Through a detailed analysis of two key application areas of ML in modern biological research - protein structure prediction and single cell RNA-sequencing - we explore how these features have thus far enabled ML systems to advance scientific understanding of their target phenomena, how they may guide the development of future ML models, and the key obstacles that remain in preventing ML from achieving its potential as a tool for biological discovery. Consideration of the epistemological features of ML applications in biology will improve the prospects of these methods to solve important problems and advance scientific understanding of living systems.

In biological research, fluorescence staining is a key technique to reveal the locations and morphology of subcellular structures. However, it is slow, expensive, and harmful to cells. In this paper, we model it as a deep learning task termed subcellular structure prediction (SSP), aiming to predict the 3D fluorescent images of multiple subcellular structures from a 3D transmitted-light image. Unfortunately, due to the limitations of current biotechnology, each image is partially labeled in SSP. Besides, naturally, subcellular structures vary considerably in size, which causes the multi-scale issue of SSP. To overcome these challenges, we propose Re-parameterizing Mixture-of-Diverse-Experts (RepMode), a network that dynamically organizes its parameters with task-aware priors to handle specified single-label prediction tasks. In RepMode, the Mixture-of-Diverse-Experts (MoDE) block is designed to learn the generalized parameters for all tasks, and gating re-parameterization (GatRep) is performed to generate the specialized parameters for each task, by which RepMode can maintain a compact practical topology exactly like a plain network, and meanwhile achieves a powerful theoretical topology. Comprehensive experiments show that RepMode can achieve state-of-the-art overall performance in SSP.