Daily Papers

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.

Driven by new types of wireless devices and the proliferation of bandwidth-intensive applications, data traffic and the corresponding network load are increasing dramatically. Network densification has been recognized as a promising and efficient way to provide higher network capacity and enhanced coverage. Most prior work on performance analysis of ultra-dense networks (UDNs) has focused on random spatial deployment with idealized singular path loss models and Rayleigh fading. In this paper, we consider a more precise and general model, which incorporates multi-slope path loss and general fading distributions. We derive the tail behavior and scaling laws for the coverage probability and the capacity considering strongest base station association in a Poisson field network. Our analytical results identify the regimes in which the signal-to-interference-plus-noise ratio (SINR) either asymptotically grows, saturates, or decreases with increasing network density. We establish general results on when UDNs lead to worse or even zero SINR coverage and capacity, and we provide crisp insights on the fundamental limits of wireless network densification.

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.

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.

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.

Predicting the intermediate trajectories between an initial and target distribution is a central problem in generative modeling. Existing approaches, such as flow matching and Schr\"odinger Bridge Matching, effectively learn mappings between two distributions by modeling a single stochastic path. However, these methods are inherently limited to unimodal transitions and cannot capture branched or divergent evolution from a common origin to multiple distinct outcomes. To address this, we introduce Branched Schr\"odinger Bridge Matching (BranchSBM), a novel framework that learns branched Schr\"odinger bridges. BranchSBM parameterizes multiple time-dependent velocity fields and growth processes, enabling the representation of population-level divergence into multiple terminal distributions. We show that BranchSBM is not only more expressive but also essential for tasks involving multi-path surface navigation, modeling cell fate bifurcations from homogeneous progenitor states, and simulating diverging cellular responses to perturbations.

The quickly increasing data traffic and the user demand for a full coverage of mobile services anywhere and anytime are leading mobile networking into a future of small cell networks. However, due to the high-density and randomness of small cell networks, there are several technical challenges. In this paper, we investigate two critical issues: best signal quality and mobility management. Under the assumptions that base stations are uniformly distributed in a ring shaped region and that shadowings are lognormal, independent and identically distributed, we prove that when the number of sites in the ring tends to infinity, then (i) the maximum signal strength received at the center of the ring tends in distribution to a Gumbel distribution when properly renormalized, and (ii) it is asymptotically independent of the interference. Using these properties, we derive the distribution of the best signal quality. Furthermore, an optimized random cell scanning scheme is proposed, based on the evaluation of the optimal number of sites to be scanned for maximizing the user data throughput.

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.

Many real-world problems require reasoning across multiple scales, demanding models which operate not on single data points, but on entire distributions. We introduce generative distribution embeddings (GDE), a framework that lifts autoencoders to the space of distributions. In GDEs, an encoder acts on sets of samples, and the decoder is replaced by a generator which aims to match the input distribution. This framework enables learning representations of distributions by coupling conditional generative models with encoder networks which satisfy a criterion we call distributional invariance. We show that GDEs learn predictive sufficient statistics embedded in the Wasserstein space, such that latent GDE distances approximately recover the W_2 distance, and latent interpolation approximately recovers optimal transport trajectories for Gaussian and Gaussian mixture distributions. We systematically benchmark GDEs against existing approaches on synthetic datasets, demonstrating consistently stronger performance. We then apply GDEs to six key problems in computational biology: learning representations of cell populations from lineage-tracing data (150K cells), predicting perturbation effects on single-cell transcriptomes (1M cells), predicting perturbation effects on cellular phenotypes (20M single-cell images), modeling tissue-specific DNA methylation patterns (253M sequences), designing synthetic yeast promoters (34M sequences), and spatiotemporal modeling of viral protein sequences (1M sequences).

The simulation of the metabolism in mammalian cells becomes a severe problem if spatial distributions must be taken into account. Especially the cytoplasm has a very complex geometric structure which cannot be handled by standard discretization techniques. In the present paper we propose a homogenization technique for computing effective diffusion constants. This is accomplished by using a two-step strategy. The first step consists of an analytic homogenization from the smallest to an intermediate scale. The homogenization error is estimated by comparing the analytic diffusion constant with a numerical estimate obtained by using real cell geometries. The second step consists of a random homogenization. Since no analytical solution is known to this homogenization problem, a numerical approximation algorithm is proposed. Although rather expensive this algorithm provides a reasonable estimate of the homogenized diffusion constant.

Straight line equation y=mx with slope m, when singularly perturbed as ay^3+y=mx with a positive parameter a, results in S-shaped curves or S-curves on a real plane. As arightarrow 0, we get back y=mx which is a cumulative distribution function of a continuous uniform distribution that describes the occurrence of every event in an interval to be equally probable. As arightarrowinfty, the derivative of y has finite support only at y=0 resembling a degenerate distribution. Based on these arguments, in this work, we propose that these S-curves can represent maximum entropy uniform distribution to a zero entropy single value. We also argue that these S-curves are superposable as they are only parametrically nonlinear but fundamentally linear. So far, the superposed forms have been used to capture the patterns of natural systems such as nonlinear dynamics of biological growth and kinetics of enzyme reactions. Here, we attempt to use the S-curve and its superposed form as statistical models. We fit the models on a classical dataset containing flower measurements of iris plants and analyze their usefulness in pattern recognition. Based on these models, we claim that any non-uniform pattern can be represented as a singular perturbation to uniform distribution. However, our parametric estimation procedure have some limitations such as sensitivity to initial conditions depending on the data at hand.

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.

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.

Building a virtual cell capable of accurately simulating cellular behaviors in silico has long been a dream in computational biology. We introduce CellFlux, an image-generative model that simulates cellular morphology changes induced by chemical and genetic perturbations using flow matching. Unlike prior methods, CellFlux models distribution-wise transformations from unperturbed to perturbed cell states, effectively distinguishing actual perturbation effects from experimental artifacts such as batch effects -- a major challenge in biological data. Evaluated on chemical (BBBC021), genetic (RxRx1), and combined perturbation (JUMP) datasets, CellFlux generates biologically meaningful cell images that faithfully capture perturbation-specific morphological changes, achieving a 35% improvement in FID scores and a 12% increase in mode-of-action prediction accuracy over existing methods. Additionally, CellFlux enables continuous interpolation between cellular states, providing a potential tool for studying perturbation dynamics. These capabilities mark a significant step toward realizing virtual cell modeling for biomedical research. Project page: https://yuhui-zh15.github.io/CellFlux/.

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.

Ocean scientists have been collecting visual data to study marine organisms for decades. These images and videos are extremely valuable both for basic science and environmental monitoring tasks. There are tools for automatically processing these data, but none that are capable of handling the extreme variability in sample populations, image quality, and habitat characteristics that are common in visual sampling of the ocean. Such distribution shifts can occur over very short physical distances and in narrow time windows. Creating models that are able to recognize when an image or video sequence contains a new organism, an unusual collection of animals, or is otherwise out-of-sample is critical to fully leverage visual data in the ocean. The FathomNet2023 competition dataset presents a realistic scenario where the set of animals in the target data differs from the training data. The challenge is both to identify the organisms in a target image and assess whether it is out-of-sample.

Understanding how deep learning models predict oncology patient risk can provide critical insights into disease progression, support clinical decision-making, and pave the way for trustworthy and data-driven precision medicine. Building on recent advances in the spatial modeling of the tumor microenvironment using graph neural networks, we present an explainable cell graph (xCG) approach for survival prediction. We validate our model on a public cohort of imaging mass cytometry (IMC) data for 416 cases of lung adenocarcinoma. We explain survival predictions in terms of known phenotypes on the cell level by computing risk attributions over cell graphs, for which we propose an efficient grid-based layer-wise relevance propagation (LRP) method. Our ablation studies highlight the importance of incorporating the cancer stage and model ensembling to improve the quality of risk estimates. Our xCG method, together with the IMC data, is made publicly available to support further research.

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)).

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.

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.

Selecting appropriate datasets is critical in modern computer vision. However, no general-purpose tools exist to evaluate the extent to which two datasets differ. For this, we propose representing images - and by extension datasets - using Distributions of Neuron Activations (DNAs). DNAs fit distributions, such as histograms or Gaussians, to activations of neurons in a pre-trained feature extractor through which we pass the image(s) to represent. This extractor is frozen for all datasets, and we rely on its generally expressive power in feature space. By comparing two DNAs, we can evaluate the extent to which two datasets differ with granular control over the comparison attributes of interest, providing the ability to customise the way distances are measured to suit the requirements of the task at hand. Furthermore, DNAs are compact, representing datasets of any size with less than 15 megabytes. We demonstrate the value of DNAs by evaluating their applicability on several tasks, including conditional dataset comparison, synthetic image evaluation, and transfer learning, and across diverse datasets, ranging from synthetic cat images to celebrity faces and urban driving scenes.

We introduce a general, flexible, parametric survival modelling framework which encompasses key shapes of hazard function (constant, increasing, decreasing, up-then-down, down-then-up), various common survival distributions (log-logistic, Burr type XII, Weibull, Gompertz), and includes defective distributions (i.e., cure models). This generality is achieved using four basic distributional parameters: two scale-type parameters and two shape parameters. Generalising to covariate dependence, the scale-type regression components correspond to accelerated failure time (AFT) and proportional hazards (PH) models. Therefore, this general formulation unifies the most popular survival models which allows us to consider the practical value of possible modelling choices for survival data. Furthermore, in line with our proposed flexible baseline distribution, we advocate the use of multi-parameter regression in which more than one distributional parameter depends on covariates - rather than the usual convention of having a single covariate-dependent (scale) parameter. While many choices are available, we suggest introducing covariates through just one or other of the two scale parameters, which covers AFT and PH models, in combination with a `power' shape parameter, which allows for more complex non-AFT/non-PH effects, while the other shape parameter remains covariate-independent, and handles automatic selection of the baseline distribution. We explore inferential issues in simulations, both with and without a covariate, with particular focus on evidence concerning the need, or otherwise, to include both AFT and PH parameters. We illustrate the efficacy of our modelling framework by investigating differences between treatment groups using data from a lung cancer study and a melanoma study. Censoring is accommodated throughout.

Estimating single-cell responses across various perturbations facilitates the identification of key genes and enhances drug screening, significantly boosting experimental efficiency. However, single-cell sequencing is a destructive process, making it impossible to capture the same cell's phenotype before and after perturbation. Consequently, data collected under perturbed and unperturbed conditions are inherently unpaired. Existing methods either attempt to forcibly pair unpaired data using random sampling, or neglect the inherent relationship between unperturbed and perturbed cells during the modeling. In this work, we propose a framework based on Dual Diffusion Implicit Bridges (DDIB) to learn the mapping between different data distributions, effectively addressing the challenge of unpaired data. We further interpret this framework as a form of data augmentation. We integrate gene regulatory network (GRN) information to propagate perturbation signals in a biologically meaningful way, and further incorporate a masking mechanism to predict silent genes, improving the quality of generated profiles. Moreover, gene expression under the same perturbation often varies significantly across cells, frequently exhibiting a bimodal distribution that reflects intrinsic heterogeneity. To capture this, we introduce a more suitable evaluation metric. We propose Unlasting, dual conditional diffusion models that overcome the problem of unpaired single-cell perturbation data and strengthen the model's insight into perturbations under the guidance of the GRN, with a dedicated mask model designed to improve generation quality by predicting silent genes. In addition, we introduce a biologically grounded evaluation metric that better reflects the inherent heterogeneity in single-cell responses.

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.

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

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.

Predicting spatial gene expression from H&E histology offers a scalable and clinically accessible alternative to sequencing, but realizing clinical impact requires models that generalize across cancer types and capture biologically coherent signals. Prior work is often limited to per-cancer settings and variance-based evaluation, leaving functional relevance underexplored. We introduce HistoPrism, an efficient transformer-based architecture for pan-cancer prediction of gene expression from histology. To evaluate biological meaning, we introduce a pathway-level benchmark, shifting assessment from isolated gene-level variance to coherent functional pathways. HistoPrism not only surpasses prior state-of-the-art models on highly variable genes , but also more importantly, achieves substantial gains on pathway-level prediction, demonstrating its ability to recover biologically coherent transcriptomic patterns. With strong pan-cancer generalization and improved efficiency, HistoPrism establishes a new standard for clinically relevant transcriptomic modeling from routinely available histology.

Sparse autoencoders (SAEs) emerged as a promising tool for mechanistic interpretability of transformer-based foundation models. Very recently, SAEs were also adopted for the visual domain, enabling the discovery of visual concepts and their patch-wise attribution to tokens in the transformer model. While a growing number of foundation models emerged for medical imaging, tools for explaining their inferences are still lacking. In this work, we show the applicability of SAEs for hematology. We propose CytoSAE, a sparse autoencoder which is trained on over 40,000 peripheral blood single-cell images. CytoSAE generalizes to diverse and out-of-domain datasets, including bone marrow cytology, where it identifies morphologically relevant concepts which we validated with medical experts. Furthermore, we demonstrate scenarios in which CytoSAE can generate patient-specific and disease-specific concepts, enabling the detection of pathognomonic cells and localized cellular abnormalities at the patch level. We quantified the effect of concepts on a patient-level AML subtype classification task and show that CytoSAE concepts reach performance comparable to the state-of-the-art, while offering explainability on the sub-cellular level. Source code and model weights are available at https://github.com/dynamical-inference/cytosae.

Cell tracking is a subject of active research gathering great interest in medicine and biology. Positron emission tomography (PET) is well suited for tracking radio-labeled cells in vivo due to its exceptional sensitivity and whole-body capability. For validation, ground-truth data are desirable that realistically mimic the flow of cells in a clinical situation. This study develops a workflow (CeFloPS) for simulating moving radio-labeled cells in a human phantom. From the XCAT phantom, the blood vessels are reduced to nodal networks along which cells can move and distribute to organs and tissues. The movement is directed by the blood flow, which is calculated in each node using the Hagen-Pooiseuille equation and Kirchhoff's laws assuming laminar flow. Organs are voxelized and movement of cells from artery entry to vein exit is generated via a biased 3D random walk. The probabilities of cells moving or remaining in tissues are derived from rate constants of tracer kinetic-based compartment modeling. PET listmode data is generated using the Monte-Carlo simulation framework GATE based on the definition of a large-body PET scanner with cell paths as moving radioactive sources and the XCAT phantom providing attenuation data. From the flow simulation of 100,000 cells, 100 sample cells were further processed by GATE and listmode data was reconstructed into images for comparison. As demonstrated by comparisons of simulated and reconstructed cell distributions, CeFloPS is capable of simulating cell behavior in whole-body PET. It achieves this simulation in a way that is anatomically and physiologically reasonable, thereby providing valuable data for the development and validation of cell tracking algorithms.

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

A sizeable fraction of gamma-ray burst (GRB) light curves (LCs) features a sequence of peaks, which holds information on the unknown way energy is dissipated into gamma-rays over time. Traditional searches for periodic signals in GRB LCs turned out to be inconclusive, partly because they are challenging as a consequence of the short-lived, coloured-noise, and non-stationary nature of the LCs themselves. Yet, recent claims have revived the issue. We searched for periodic components in GRB LCs through a new approach to GRBs, that avoids most of the issues faced by traditional techniques. We identified peaks through a well tested algorithm and selected GRBs with at least 10 peaks out of 5 GRB catalogues (Swift/BAT, CGRO/BATSE, Fermi/GBM, Insight-HXMT, BeppoSAX/GRBM). Each GRB was simply treated as a discrete point process, whose realisation coincides with the sequence of peak times. We searched for possible periodic recurrences based on the multinomial distribution, after accounting for the clustering of peaks due to the non-stationarity of the GRB signals. The best candidate has a p-value of 3e-4 that there is no periodic recurrence. However, accounting for the multiple trials of 555 searched GRBs, its statistical significance is demoted to 17%. The overall distribution of the p-values obtained for all GRBs is compatible with a uniform distribution in [0,1]. We found no robust evidence for multi-peaked GRBs with periodic recurrences. We can exclude that a sizeable fraction (>~ 0.75) of peaks of each GRB with at least 10 peaks are periodic. While our result does not necessarily clash with claimed periodicities based on Fourier techniques, it constrains the putative recurrent behaviour, which would not manifest itself through the sequence of peaks, but, evidently, in a more elusive way.

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.

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.

Molecules are frequently represented as graphs, but the underlying 3D molecular geometry (the locations of the atoms) ultimately determines most molecular properties. However, most molecules are not static and at room temperature adopt a wide variety of geometries or conformations. The resulting distribution on geometries p(x) is known as the Boltzmann distribution, and many molecular properties are expectations computed under this distribution. Generating accurate samples from the Boltzmann distribution is therefore essential for computing these expectations accurately. Traditional sampling-based methods are computationally expensive, and most recent machine learning-based methods have focused on identifying modes in this distribution rather than generating true samples. Generating such samples requires capturing conformational variability, and it has been widely recognized that the majority of conformational variability in molecules arises from rotatable bonds. In this work, we present VonMisesNet, a new graph neural network that captures conformational variability via a variational approximation of rotatable bond torsion angles as a mixture of von Mises distributions. We demonstrate that VonMisesNet can generate conformations for arbitrary molecules in a way that is both physically accurate with respect to the Boltzmann distribution and orders of magnitude faster than existing sampling methods.

Collections of probability distributions arise in a variety of applications ranging from user activity pattern analysis to brain connectomics. In practice these distributions can be defined over diverse domain types including finite intervals, circles, cylinders, spheres, other manifolds, and graphs. This paper introduces an approach for detecting differences between two collections of distributions over such general domains. To this end, we propose the intrinsic slicing construction that yields a novel class of Wasserstein distances on manifolds and graphs. These distances are Hilbert embeddable, allowing us to reduce the distribution collection comparison problem to a more familiar mean testing problem in a Hilbert space. We provide two testing procedures one based on resampling and another on combining p-values from coordinate-wise tests. Our experiments in various synthetic and real data settings show that the resulting tests are powerful and the p-values are well-calibrated.

In this work we introduce a physically motivated method of performing disc/spheroid decomposition of simulated galaxies, which we apply to the Eagle sample. We make use of the HEALPix package to create Mollweide projections of the angular momentum map of each galaxy's stellar particles. A number of features arise on the angular momentum space which allows us to decompose galaxies and classify them into different morphological types. We assign stellar particles with angular separation of less/greater than 30 degrees from the densest grid cell on the angular momentum sphere to the disc/spheroid components, respectively. We analyse the spatial distribution for a subsample of galaxies and show that the surface density profiles of the disc and spheroid closely follow an exponential and a Sersic profile, respectively. In addition discs rotate faster, have smaller velocity dispersions, are younger and are more metal rich than spheroids. Thus our morphological classification reproduces the observed properties of such systems. Finally, we demonstrate that our method is able to identify a significant population of galaxies with counter-rotating discs and provide a more realistic classification of such systems compared to previous methods.

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.

The distribution of subpopulations is an important property hidden within a dataset. Uncovering and analyzing the subpopulation distribution within datasets provides a comprehensive understanding of the datasets, standing as a powerful tool beneficial to various downstream tasks, including Dataset Subpopulation Organization, Subpopulation Shift, and Slice Discovery. Despite its importance, there has been no work that systematically explores the subpopulation distribution of datasets to our knowledge. To address the limitation and solve all the mentioned tasks in a unified way, we introduce a novel concept of subpopulation structures to represent, analyze, and utilize subpopulation distributions within datasets. To characterize the structures in an interpretable manner, we propose the Subpopulation Structure Discovery with Large Language Models (SSD-LLM) framework, which employs world knowledge and instruction-following capabilities of Large Language Models (LLMs) to linguistically analyze informative image captions and summarize the structures. Furthermore, we propose complete workflows to address downstream tasks, named Task-specific Tuning, showcasing the application of the discovered structure to a spectrum of subpopulation-related tasks, including dataset subpopulation organization, subpopulation shift, and slice discovery. Furthermore, we propose complete workflows to address downstream tasks, named Task-specific Tuning, showcasing the application of the discovered structure to a spectrum of subpopulation-related tasks, including dataset subpopulation organization, subpopulation shift, and slice discovery.

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.

Mixed Integer Linear Programming (MILP) is a fundamental tool for modeling combinatorial optimization problems. Recently, a growing body of research has used machine learning to accelerate MILP solving. Despite the increasing popularity of this approach, there is a lack of a common repository that provides distributions of similar MILP instances across different domains, at different hardness levels, with standardized test sets. In this paper, we introduce Distributional MIPLIB, a multi-domain library of problem distributions for advancing ML-guided MILP methods. We curate MILP distributions from existing work in this area as well as real-world problems that have not been used, and classify them into different hardness levels. It will facilitate research in this area by enabling comprehensive evaluation on diverse and realistic domains. We empirically illustrate the benefits of using Distributional MIPLIB as a research vehicle in two ways. We evaluate the performance of ML-guided variable branching on previously unused distributions to identify potential areas for improvement. Moreover, we propose to learn branching policies from a mix of distributions, demonstrating that mixed distributions achieve better performance compared to homogeneous distributions when there is limited data and generalize well to larger instances. The dataset is publicly available at https://sites.google.com/usc.edu/distributional-miplib/home.

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.

Solar photospheric abundances and CI-chondrite compositions are reviewed and updated to obtain representative solar system abundances of the elements and their isotopes. The new photospheric abundances obtained here lead to higher solar metallicity. Full 3D NLTE photospheric analyses are only available for 11 elements. A quality index for analyses is introduced. For several elements, uncertainties remain large. Protosolar mass fractions are H (X = 0.7060), He (Y = 0.2753), and for metals Li to U (Z = 0.0187). The protosolar (C+N)/H agrees within 13% with the ratio for the solar core from the Borexino experiment. Elemental abundances in CI-chondrites were screened by analytical methods, sample sizes, and evaluated using concentration frequency distributions. Aqueously mobile elements (e.g., alkalis, alkaline earths, etc.) often deviate from normal distributions indicating mobilization and/or sequestration into carbonates, phosphates, and sulfates. Revised CI-chondrite abundances of non-volatile elements are similar to earlier estimates. The moderately volatile elements F and Sb are higher than before, as are C, Br and I, whereas the CI-abundances of Hg and N are now significantly lower. The solar system nuclide distribution curves of s-process elements agree within 4% with s-process predictions of Galactic chemical evolution models. P-process nuclide distributions are assessed. No obvious correlation of CI-chondritic to solar elemental abundance ratios with condensation temperatures is observed, nor is there one for ratios of CI-chondrites/solar wind abundances.

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.

Nasal Cytology is a new and efficient clinical technique to diagnose rhinitis and allergies that is not much widespread due to the time-consuming nature of cell counting; that is why AI-aided counting could be a turning point for the diffusion of this technique. In this article we present the first dataset of rhino-cytological field images: the NCD (Nasal Cytology Dataset), aimed to train and deploy Object Detection models to support physicians and biologists during clinical practice. The real distribution of the cytotypes, populating the nasal mucosa has been replicated, sampling images from slides of clinical patients, and manually annotating each cell found on them. The correspondent object detection task presents non'trivial issues associated with the strong class imbalancement, involving the rarest cell types. This work contributes to some of open challenges by presenting a novel machine learning-based approach to aid the automated detection and classification of nasal mucosa cells: the DETR and YOLO models shown good performance in detecting cells and classifying them correctly, revealing great potential to accelerate the work of rhinology experts.

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.

Context. Understanding how the shape of cloud particle size distributions affects the atmospheric properties of sub-stellar atmospheres is a key area to explore, particularly in the JWST era of broad wavelength coverage, where observations are sensitive to particle size distributions. It is therefore important to elucidate how underlying cloud microphysical processes influence the size distribution, in order to better understand how clouds affect observed atmospheric properties. Aims. In this follow-up paper, we aim to extend our sub-stellar atmosphere microphysical cloud formation framework from Paper I to include effects of assuming a polydisperse gamma particle size distribution, requiring a three-moment solution set of equations. Methods. We develop a three-moment framework for sub-stellar mineral cloud particle microphysical nucleation, condensation, evaporation and collisional growth assuming a gamma distribution. As in the previous paper, we demonstrate the effects of polydispersity using a simple one-dimensional Y-dwarf KCl cloud formation scenario, and compare the results with the monodisperse case. Results. Our three-moment scheme provides a generalised framework applicable to any size distribution with a defined moment generation expression. In our test case, we show that the gamma distribution evolves with altitude, initially broad at the cloud base and narrowing at lower pressures. We find that differences between the gamma and monodisperse cloud structures can be significant, depending on the surface gravity of the atmosphere. Conclusions. We present a self-consistent framework for including the effects of polydispersity for sub-stellar microphysical cloud studies using the moment method.

Feature attribution methods identify which features of an input most influence a model's output. Most widely-used feature attribution methods (such as SHAP, LIME, and Grad-CAM) are "class-dependent" methods in that they generate a feature attribution vector as a function of class. In this work, we demonstrate that class-dependent methods can "leak" information about the selected class, making that class appear more likely than it is. Thus, an end user runs the risk of drawing false conclusions when interpreting an explanation generated by a class-dependent method. In contrast, we introduce "distribution-aware" methods, which favor explanations that keep the label's distribution close to its distribution given all features of the input. We introduce SHAP-KL and FastSHAP-KL, two baseline distribution-aware methods that compute Shapley values. Finally, we perform a comprehensive evaluation of seven class-dependent and three distribution-aware methods on three clinical datasets of different high-dimensional data types: images, biosignals, and text.

Many methods have been proposed for removing batch effects and aligning single-cell RNA (scRNA) datasets. However, performance is typically evaluated based on multiple parameters and few datasets, creating challenges in assessing which method is best for aligning data at scale. Here, we introduce the K-Neighbors Intersection (KNI) score, a single score that both penalizes batch effects and measures accuracy at cross-dataset cell-type label prediction alongside carefully curated small (scMARK) and large (scREF) benchmarks comprising 11 and 46 human scRNA studies respectively, where we have standardized author labels. Using the KNI score, we evaluate and optimize approaches for cross-dataset single-cell RNA integration. We introduce Batch Adversarial single-cell Variational Inference (BA-scVI), as a new variant of scVI that uses adversarial training to penalize batch-effects in the encoder and decoder, and show this approach outperforms other methods. In the resulting aligned space, we find that the granularity of cell-type groupings is conserved, supporting the notion that whole-organism cell-type maps can be created by a single model without loss of information.

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.

Spatial proteomics technologies have transformed our understanding of complex tissue architectures by enabling simultaneous analysis of multiple molecular markers and their spatial organization. The high dimensionality of these data, varying marker combinations across experiments and heterogeneous study designs pose unique challenges for computational analysis. Here, we present Virtual Tissues (VirTues), a foundation model framework for biological tissues that operates across the molecular, cellular and tissue scale. VirTues introduces innovations in transformer architecture design, including a novel tokenization scheme that captures both spatial and marker dimensions, and attention mechanisms that scale to high-dimensional multiplex data while maintaining interpretability. Trained on diverse cancer and non-cancer tissue datasets, VirTues demonstrates strong generalization capabilities without task-specific fine-tuning, enabling cross-study analysis and novel marker integration. As a generalist model, VirTues outperforms existing approaches across clinical diagnostics, biological discovery and patient case retrieval tasks, while providing insights into tissue function and disease mechanisms.

We introduce a new -- currently 42 gigabyte -- ``living'' dataset of phone images of dog feces, annotated with manually drawn or AI-assisted polygon labels. There are 6k full resolution images and 4k detailed polygon annotations. The collection and annotation of images started in late 2020 and the dataset grows by roughly 1GB a month. We train VIT and MaskRCNN baseline models to explore the difficulty of the dataset. The best model achieves a pixelwise average precision of 0.858 on a 691-image validation set and 0.847 on a small independently captured 30-image contributor test set. The most recent snapshot of dataset is made publicly available through three different distribution methods: one centralized (Girder) and two decentralized (IPFS and BitTorrent). We study of the trade-offs between distribution methods and discuss the feasibility of each with respect to reliably sharing open scientific data. The code to reproduce the experiments is hosted on GitHub, and the data is published under the Creative Commons Attribution 4.0 International license. Model weights are made publicly available with the dataset. Experimental hardware, time, energy, and emissions are quantified.

TRPM4 is overexpressed in prostate cancer (PCa) associated with metastasis or recurrence. There is paucity of information pertaining to TRPM4 characterization and functions at single-cell level in PCa. In this study, generalized additive model (GAM) was utilized to model the relationship between TRPM4 and genes shortlisted using Spearman-Kendall dual-filter in aggressive PCa and benign prostate (BP) control cells derived from scRNA-seq dataset. Seven ribosomal genes (RPL10, RPL27, RPL28, RPS2, RPS8, RPS12, and RPS26; averaged into Ribo as the gene set), passed the dual-filter specifically in PCa cells. GAM modeling of TRPM4-Ribo significantly outperformed TRPM4 modeling with alternative cancer gene sets (GSK-3B, mTOR, NF-KB, PI3K/AKT, and Wnt). Cell explanatory power (CEP) classification was devised and verified by cross-validation to identify individual PCa cells most well-predicted by the model. CEP classification binarized PCa cells into top-ranked explanatory power (TREP; more well-predicted by the model) and non-TREP cells. In TRPM4-Ribo GAM plots, distribution pattern of TREP cells shifted at an inflection point (IP) i.e., the specific TRPM4 expression value that further binarized the plot into pre-IP (TRPM4 values below IP) and post-IP (TRPM4 values above IP) regions, producing a quadrant of TREP versus non-TREP cells for each PCa patient. Gene Ontology (GO) enrichment analysis showed that pre-IP TREP cells enriched for immune-related GOs, while post-IP TREP cells enriched for ribosomal, translation, and cell adhesion GOs. In conclusion, the CEP-IP framework based on pairwise genes produces quadrants of cancer cell subpopulations, enabling the identification of distinctive biology with potential therapeutic implications.

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.

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.

Cancer is a genetic disorder whose clonal evolution can be monitored by tracking noisy genome-wide copy number variants. We introduce the Copy Number Stochastic Block Model (CN-SBM), a probabilistic framework that jointly clusters samples and genomic regions based on discrete copy number states using a bipartite categorical block model. Unlike models relying on Gaussian or Poisson assumptions, CN-SBM respects the discrete nature of CNV calls and captures subpopulation-specific patterns through block-wise structure. Using a two-stage approach, CN-SBM decomposes CNV data into primary and residual components, enabling detection of both large-scale chromosomal alterations and finer aberrations. We derive a scalable variational inference algorithm for application to large cohorts and high-resolution data. Benchmarks on simulated and real datasets show improved model fit over existing methods. Applied to TCGA low-grade glioma data, CN-SBM reveals clinically relevant subtypes and structured residual variation, aiding patient stratification in survival analysis. These results establish CN-SBM as an interpretable, scalable framework for CNV analysis with direct relevance for tumor heterogeneity and prognosis.

Fluorescence Lifetime Imaging (FLI) is a critical molecular imaging modality that provides unique information about the tissue microenvironment, which is invaluable for biomedical applications. FLI operates by acquiring and analyzing photon time-of-arrival histograms to extract quantitative parameters associated with temporal fluorescence decay. These histograms are influenced by the intrinsic properties of the fluorophore, instrument parameters, time-of-flight distributions associated with pixel-wise variations in the topographic and optical characteristics of the sample. Recent advancements in Deep Learning (DL) have enabled improved fluorescence lifetime parameter estimation. However, existing models are primarily designed for planar surface samples, limiting their applicability in translational scenarios involving complex surface profiles, such as in-vivo whole-animal or imaged guided surgical applications. To address this limitation, we present MFliNet (Macroscopic FLI Network), a novel DL architecture that integrates the Instrument Response Function (IRF) as an additional input alongside experimental photon time-of-arrival histograms. Leveraging the capabilities of a Differential Transformer encoder-decoder architecture, MFliNet effectively focuses on critical input features, such as variations in photon time-of-arrival distributions. We evaluate MFliNet using rigorously designed tissue-mimicking phantoms and preclinical in-vivo cancer xenograft models. Our results demonstrate the model's robustness and suitability for complex macroscopic FLI applications, offering new opportunities for advanced biomedical imaging in diverse and challenging settings.

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.

Neural representations of 3D data have been widely adopted across various applications, particularly in recent work leveraging coordinate-based networks to model scalar or vector fields. However, these approaches face inherent challenges, such as handling thin structures and non-watertight geometries, which limit their flexibility and accuracy. In contrast, we propose a novel geometric data representation that models geometry as distributions-a powerful representation that makes no assumptions about surface genus, connectivity, or boundary conditions. Our approach uses diffusion models with a novel network architecture to learn surface point distributions, capturing fine-grained geometric details. We evaluate our representation qualitatively and quantitatively across various object types, demonstrating its effectiveness in achieving high geometric fidelity. Additionally, we explore applications using our representation, such as textured mesh representation, neural surface compression, dynamic object modeling, and rendering, highlighting its potential to advance 3D geometric learning.

In optimal transport (OT), a Monge map is known as a mapping that transports a source distribution to a target distribution in the most cost-efficient way. Recently, multiple neural estimators for Monge maps have been developed and applied in diverse unpaired domain translation tasks, e.g. in single-cell biology and computer vision. However, the classic OT framework enforces mass conservation, which makes it prone to outliers and limits its applicability in real-world scenarios. The latter can be particularly harmful in OT domain translation tasks, where the relative position of a sample within a distribution is explicitly taken into account. While unbalanced OT tackles this challenge in the discrete setting, its integration into neural Monge map estimators has received limited attention. We propose a theoretically grounded method to incorporate unbalancedness into any Monge map estimator. We improve existing estimators to model cell trajectories over time and to predict cellular responses to perturbations. Moreover, our approach seamlessly integrates with the OT flow matching (OT-FM) framework. While we show that OT-FM performs competitively in image translation, we further improve performance by incorporating unbalancedness (UOT-FM), which better preserves relevant features. We hence establish UOT-FM as a principled method for unpaired image translation.

Masked image modelling (MIM) is a powerful self-supervised representation learning paradigm, whose potential has not been widely demonstrated in medical image analysis. In this work, we show the capacity of MIM to capture rich semantic representations of Haemotoxylin & Eosin (H&E)-stained images at the nuclear level. Inspired by Bidirectional Encoder representation from Image Transformers (BEiT), we split the images into smaller patches and generate corresponding discrete visual tokens. In addition to the regular grid-based patches, typically used in visual Transformers, we introduce patches of individual cell nuclei. We propose positional encoding of the irregular distribution of these structures within an image. We pre-train the model in a self-supervised manner on H&E-stained whole-slide images of diffuse large B-cell lymphoma, where cell nuclei have been segmented. The pre-training objective is to recover the original discrete visual tokens of the masked image on the one hand, and to reconstruct the visual tokens of the masked object instances on the other. Coupling these two pre-training tasks allows us to build powerful, context-aware representations of nuclei. Our model generalizes well and can be fine-tuned on downstream classification tasks, achieving improved cell classification accuracy on PanNuke dataset by more than 5% compared to current instance segmentation methods.

Brain tumor growth is unique to each glioma patient and extends beyond what is visible in imaging scans, infiltrating surrounding brain tissue. Understanding these hidden patient-specific progressions is essential for effective therapies. Current treatment plans for brain tumors, such as radiotherapy, typically involve delineating a uniform margin around the visible tumor on pre-treatment scans to target this invisible tumor growth. This "one size fits all" approach is derived from population studies and often fails to account for the nuances of individual patient conditions. We present the GliODIL framework, which infers the full spatial distribution of tumor cell concentration from available multi-modal imaging, leveraging a Fisher-Kolmogorov type physics model to describe tumor growth. This is achieved through the newly introduced method of Optimizing the Discrete Loss (ODIL), where both data and physics-based constraints are softly assimilated into the solution. Our test dataset comprises 152 glioblastoma patients with pre-treatment imaging and post-treatment follow-ups for tumor recurrence monitoring. By blending data-driven techniques with physics-based constraints, GliODIL enhances recurrence prediction in radiotherapy planning, challenging traditional uniform margins and strict adherence to the Fisher-Kolmogorov partial differential equation (PDE) model, which is adapted for complex cases.

Recent advances in microscopy have enabled the rapid generation of terabytes of image data in cell biology and biomedical research. Vision-language models (VLMs) offer a promising solution for large-scale biological image analysis, enhancing researchers' efficiency, identifying new image biomarkers, and accelerating hypothesis generation and scientific discovery. However, there is a lack of standardized, diverse, and large-scale vision-language benchmarks to evaluate VLMs' perception and cognition capabilities in biological image understanding. To address this gap, we introduce {\mu}-Bench, an expert-curated benchmark encompassing 22 biomedical tasks across various scientific disciplines (biology, pathology), microscopy modalities (electron, fluorescence, light), scales (subcellular, cellular, tissue), and organisms in both normal and abnormal states. We evaluate state-of-the-art biomedical, pathology, and general VLMs on {\mu}-Bench and find that: i) current models struggle on all categories, even for basic tasks such as distinguishing microscopy modalities; ii) current specialist models fine-tuned on biomedical data often perform worse than generalist models; iii) fine-tuning in specific microscopy domains can cause catastrophic forgetting, eroding prior biomedical knowledge encoded in their base model. iv) weight interpolation between fine-tuned and pre-trained models offers one solution to forgetting and improves general performance across biomedical tasks. We release {\mu}-Bench under a permissive license to accelerate the research and development of microscopy foundation models.

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.

Practitioners frequently aim to infer an unobserved population trajectory using sample snapshots at multiple time points. For instance, in single-cell sequencing, scientists would like to learn how gene expression evolves over time. But sequencing any cell destroys that cell. So we cannot access any cell's full trajectory, but we can access snapshot samples from many cells. Stochastic differential equations are commonly used to analyze systems with full individual-trajectory access; since here we have only sample snapshots, these methods are inapplicable. The deep learning community has recently explored using Schr\"odinger bridges (SBs) and their extensions to estimate these dynamics. However, these methods either (1) interpolate between just two time points or (2) require a single fixed reference dynamic within the SB, which is often just set to be Brownian motion. But learning piecewise from adjacent time points can fail to capture long-term dependencies. And practitioners are typically able to specify a model class for the reference dynamic but not the exact values of the parameters within it. So we propose a new method that (1) learns the unobserved trajectories from sample snapshots across multiple time points and (2) requires specification only of a class of reference dynamics, not a single fixed one. In particular, we suggest an iterative projection method inspired by Schr\"odinger bridges; we alternate between learning a piecewise SB on the unobserved trajectories and using the learned SB to refine our best guess for the dynamics within the reference class. We demonstrate the advantages of our method via a well-known simulated parametric model from ecology, simulated and real data from systems biology, and real motion-capture data.

Single-cell transcriptomics enabled the study of cellular heterogeneity in response to perturbations at the resolution of individual cells. However, scaling high-throughput screens (HTSs) to measure cellular responses for many drugs remains a challenge due to technical limitations and, more importantly, the cost of such multiplexed experiments. Thus, transferring information from routinely performed bulk RNA HTS is required to enrich single-cell data meaningfully. We introduce chemCPA, a new encoder-decoder architecture to study the perturbational effects of unseen drugs. We combine the model with an architecture surgery for transfer learning and demonstrate how training on existing bulk RNA HTS datasets can improve generalisation performance. Better generalisation reduces the need for extensive and costly screens at single-cell resolution. We envision that our proposed method will facilitate more efficient experiment designs through its ability to generate in-silico hypotheses, ultimately accelerating drug discovery.

A model involving Gaussian processes (GPs) is introduced to simultaneously handle multi-task learning, clustering, and prediction for multiple functional data. This procedure acts as a model-based clustering method for functional data as well as a learning step for subsequent predictions for new tasks. The model is instantiated as a mixture of multi-task GPs with common mean processes. A variational EM algorithm is derived for dealing with the optimisation of the hyper-parameters along with the hyper-posteriors' estimation of latent variables and processes. We establish explicit formulas for integrating the mean processes and the latent clustering variables within a predictive distribution, accounting for uncertainty on both aspects. This distribution is defined as a mixture of cluster-specific GP predictions, which enhances the performances when dealing with group-structured data. The model handles irregular grid of observations and offers different hypotheses on the covariance structure for sharing additional information across tasks. The performances on both clustering and prediction tasks are assessed through various simulated scenarios and real datasets. The overall algorithm, called MagmaClust, is publicly available as an R package.

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.

Network densification is a promising cellular deployment technique that leverages spatial reuse to enhance coverage and throughput. Recent work has identified that at some point ultra-densification will no longer be able to deliver significant throughput gains. In this paper, we provide a unified treatment of the performance limits of network densification. We develop a general framework, which incorporates multi-slope pathloss and the entire space of shadowing and small scale fading distributions, under strongest cell association in a Poisson field of interferers. First, our results show that there are three scaling regimes for the downlink signal-to-interference-plus-noise ratio (SINR), coverage probability, and average per-user rate. Specifically, depending on the near-field pathloss and the fading distribution, the user performance of 5G ultra dense networks (UDNs) would either monotonically increase, saturate, or decay with increasing network density. Second, we show that network performance in terms of coverage density and area spectral efficiency can scale with the network density better than the user performance does. Furthermore, we provide ordering results for both coverage and average rate as a means to qualitatively compare different transmission techniques that may exhibit the same performance scaling. Our results, which are verified by simulations, provide succinct insights and valuable design guidelines for the deployment of 5G UDNs.

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.