Daily Papers

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

The Transatomic Power (TAP) reactor has an unusual design for a molten salt reactor technology, building upon the foundation laid by the Molten Salt Reactor Experiment (MSRE). This design introduces three key modifications to enhance efficiency and compactness: a revised fuel salt composition, an alternative moderator material, and moderator pins surrounded by the molten salt fuel. Unlike traditional solid-fueled reactors that rely on excess positive reactivity at the beginning of life, the TAP concept employs a dynamic approach. The core's design, featuring a cylindrical geometry with square assemblies of moderator rods surrounded by flowing fuel salt, provides flexibility in adjusting the moderator-to-fuel ratio during operation - using movable moderator rods - further adding criticality control capability in addition to the control rods system. Shape optimization of the core can play a crucial role in enhancing performance and efficiency. By applying multiphysics continuous shape optimization techniques to key components, such as the unit cells of the TAP reactor or its moderator assemblies, we can fine-tune the reactor's geometry to achieve optimal performance in key physics like neutronics and thermal hydraulics. We explore this aspect using the optimization module in the Multiphysics Object Oriented Simulation Environment (MOOSE) framework which allows for multiphysics continuous shape optimization. The results reported here illustrate the benefits of applying continuous shape optimization in the design of nuclear reactor components and can help in extending the TAP reactor's performance.

Crystal structures are characterized by atomic bases within a primitive unit cell that repeats along a regular lattice throughout 3D space. The periodic and infinite nature of crystals poses unique challenges for geometric graph representation learning. Specifically, constructing graphs that effectively capture the complete geometric information of crystals and handle chiral crystals remains an unsolved and challenging problem. In this paper, we introduce a novel approach that utilizes the periodic patterns of unit cells to establish the lattice-based representation for each atom, enabling efficient and expressive graph representations of crystals. Furthermore, we propose ComFormer, a SE(3) transformer designed specifically for crystalline materials. ComFormer includes two variants; namely, iComFormer that employs invariant geometric descriptors of Euclidean distances and angles, and eComFormer that utilizes equivariant vector representations. Experimental results demonstrate the state-of-the-art predictive accuracy of ComFormer variants on various tasks across three widely-used crystal benchmarks. Our code is publicly available as part of the AIRS library (https://github.com/divelab/AIRS).

Generative models for materials, especially inorganic crystals, hold potential to transform the theoretical prediction of novel compounds and structures. Advancement in this field depends critically on robust benchmarks and minimal, information-rich datasets that enable meaningful model evaluation. This paper critically examines common datasets and reported metrics for a crystal structure prediction taskx2014generating the most likely structures given the chemical composition of a material. We focus on three key issues: First, materials datasets should contain unique crystal structures; for example, we show that the widely-utilized carbon-24 dataset only contains approx40% unique structures. Second, materials datasets should not be split randomly if polymorphs of many different compositions are numerous, which we find to be the case for the perov-5 dataset. Third, benchmarks can mislead if used uncritically, e.g., reporting a match rate metric without considering the structural variety exhibited by identical building blocks. To address these oft-overlooked issues, we introduce several fixes. We provide revised versions of the carbon-24 dataset: one with duplicates removed, one deduplicated and split by number of atoms N, and two containing only identical structures but with different unit cells. We also propose a new split for the perov-5 dataset which ensures polymorphs are grouped within each split subset, setting a more sensible standard for benchmarking model performance. Finally, we present METRe and cRMSE, new model evaluation metrics that can correct existing issues with the match rate metric.

Robotic systems operating in unstructured environments require the ability to switch between compliant and rigid states to perform diverse tasks such as adaptive grasping, high-force manipulation, shape holding, and navigation in constrained spaces, among others. However, many existing variable stiffness solutions rely on complex actuation schemes, continuous input power, or monolithic designs, limiting their modularity and scalability. This paper presents the Programmable Locking Cell (PLC)-a modular, tendon-driven unit that achieves discrete stiffness modulation through mechanically interlocked joints actuated by cable tension. Each unit transitions between compliant and firm states via structural engagement, and the assembled system exhibits high stiffness variation-up to 950% per unit-without susceptibility to damage under high payload in the firm state. Multiple PLC units can be assembled into reconfigurable robotic structures with spatially programmable stiffness. We validate the design through two functional prototypes: (1) a variable-stiffness gripper capable of adaptive grasping, firm holding, and in-hand manipulation; and (2) a pipe-traversing robot composed of serial PLC units that achieves shape adaptability and stiffness control in confined environments. These results demonstrate the PLC as a scalable, structure-centric mechanism for programmable stiffness and motion, enabling robotic systems with reconfigurable morphology and task-adaptive interaction.

The fundamental units of internal representations in large language models (LLMs) remain undefined, limiting further understanding of their mechanisms. Neurons or features are often regarded as such units, yet neurons suffer from polysemy, while features face concerns of unreliable reconstruction and instability. To address this issue, we propose the Atoms Theory, which defines such units as atoms. We introduce the atomic inner product (AIP) to correct representation shifting, formally define atoms, and prove the conditions that atoms satisfy the Restricted Isometry Property (RIP), ensuring stable sparse representations over atom set and linking to compressed sensing. Under stronger conditions, we further establish the uniqueness and exact ell_1 recoverability of the sparse representations, and provide guarantees that single-layer sparse autoencoders (SAEs) with threshold activations can reliably identify the atoms. To validate the Atoms Theory, we train threshold-activated SAEs on Gemma2-2B, Gemma2-9B, and Llama3.1-8B, achieving 99.9% sparse reconstruction across layers on average, and more than 99.8% of atoms satisfy the uniqueness condition, compared to 0.5% for neurons and 68.2% for features, showing that atoms more faithfully capture intrinsic representations of LLMs. Scaling experiments further reveal the link between SAEs size and recovery capacity. Overall, this work systematically introduces and validates Atoms Theory of LLMs, providing a theoretical framework for understanding internal representations and a foundation for mechanistic interpretability. Code available at https://github.com/ChenhuiHu/towards_atoms.

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.

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.

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.

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.

We present a generative framework for inverse design of five-layer transmissive Huygens' metasurfaces (HMSs), addressing a longstanding challenge in achieving full-phase, high-efficiency unit cell designs with minimal full-wave simulations. The key to achieving this is our reliance on the field-based semianalytical (SA) scheme developed in Part I of this paper, which allows rapid and highly effective synthesis of such multilayer composites, however with limited accuracy. To overcome the prohibitive data demands of traditional pipelines, we employ Mamba, a selective state space model well suited for long-range sequence modeling as the backbone of our learning framework. A bidirectional Mamba (Bi-Mamba) forward surrogate is first trained on SA-generated data and subsequently fine-tuned with full-wave CST samples. An ablation over a 1080-sample CST pool shows that as few as 270 full-wave calibration samples suffice to reach near-CST-level agreement at a fraction of the simulation cost. An autoregressive Mamba inverse generator is subsequently trained on surrogate-augmented data, treating unit-cell synthesis as a sequential generation task. The resulting one-to-many generative model produces diverse unit cell geometries conditioned on target scattering responses. It achieves CST-validated designs with field transmission magnitude 0.9 across the full 0-2π phase range at 20 GHz. Moreover, a CST-calibrated surrogate trained to accurately predict frequency responses (18-22 GHz) enables functional post-selection of inverse generated designs. Together, the hybrid SA-generative methodology in this two-part compilation establishes a scalable and data-efficient solution for multilayer HMS synthesis, with natural extensions toward broadband, oblique-incidence, and higher-dimensional electromagnetic inverse-design problems.

Recent advancements in NLP have witnessed the groundbreaking impact of pretrained models, yielding impressive outcomes across various tasks. This study seeks to extend the power of pretraining methodologies to facilitating the prediction over tables in data science, a domain traditionally overlooked, yet inherently challenging due to the plethora of table schemas intrinsic to different tasks. The primary research questions underpinning this work revolve around the establishment of a universal pretraining protocol for tables with varied structures, the generalizability and transferability of learned knowledge across tasks, the adaptation to diverse downstream applications, and the incorporation of incremental columns over time. In response to these challenges, we introduce UniTabE, a straightforward yet effective method designed to process tables in a uniform manner, devoid of constraints imposed by specific table structures. UniTabE's core concept relies on representing each basic table element with a module, termed TabUnit. This is subsequently followed by a Transformer encoder to refine the representation. Moreover, our model is designed to facilitate pretraining and finetuning through the utilization of free-form prompts. In order to implement the pretraining phase, we curated an expansive tabular dataset comprising approximately 13B samples, meticulously gathered from the Kaggle platform. This research primarily centers on classification and regression tasks involving tabular data, and conducts rigorous experimental testing and analyses to validate the effectiveness of our methodology. The experimental results demonstrate UniTabE's superior performance against several baselines across massive benchmarks. This, therefore, underscores UniTabE's potential to significantly enhance the semantic representation of tabular data, thereby marking a significant stride for tabular data analysis.

The remarkable capability of large language models (LLMs) in generating high-quality code has drawn increasing attention in the software testing community. However, existing code LLMs often demonstrate unsatisfactory capabilities in generating accurate and complete tests since they were trained on code snippets collected without differentiating between code for testing purposes and other code. In this paper, we present a large-scale dataset UniTSyn, which is capable of enhancing the prowess of LLMs for Unit Test Synthesis. Associating tests with the tested functions is crucial for LLMs to infer the expected behavior and the logic paths to be verified. By leveraging Language Server Protocol, UniTSyn achieves the challenging goal of collecting focal-test pairs without per-project execution setups or per-language heuristics that tend to be fragile and difficult to scale. It contains 2.7 million focal-test pairs across five mainstream programming languages, making it possible to be utilized for enhancing the test generation ability of LLMs. The details of UniTSyn can be found in Table 1. Our experiments demonstrate that, by building an autoregressive model based on UniTSyn, we can achieve significant benefits in learning and understanding unit test representations, resulting in improved generation accuracy and code coverage across all evaluated programming languages. Code and data will be publicly available.

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.

Instance segmentation of neurons in volumetric light microscopy images of nervous systems enables groundbreaking research in neuroscience by facilitating joint functional and morphological analyses of neural circuits at cellular resolution. Yet said multi-neuron light microscopy data exhibits extremely challenging properties for the task of instance segmentation: Individual neurons have long-ranging, thin filamentous and widely branching morphologies, multiple neurons are tightly inter-weaved, and partial volume effects, uneven illumination and noise inherent to light microscopy severely impede local disentangling as well as long-range tracing of individual neurons. These properties reflect a current key challenge in machine learning research, namely to effectively capture long-range dependencies in the data. While respective methodological research is buzzing, to date methods are typically benchmarked on synthetic datasets. To address this gap, we release the FlyLight Instance Segmentation Benchmark (FISBe) dataset, the first publicly available multi-neuron light microscopy dataset with pixel-wise annotations. In addition, we define a set of instance segmentation metrics for benchmarking that we designed to be meaningful with regard to downstream analyses. Lastly, we provide three baselines to kick off a competition that we envision to both advance the field of machine learning regarding methodology for capturing long-range data dependencies, and facilitate scientific discovery in basic neuroscience.

Spintronics is expected as the next-generation technology based on the novel notch of spin degree of freedom of electrons. Half metals, a class of materials which behave as a metal in one spin direction and an insulator in the opposite spin direction, are ideal for spintronic applications. Half metallic antiferromagnets as a subclass of half metals are characterized further by totally compensated spin moments in a unit cell, and have the advantage of being able to generate fully spin-polarized current while exhibiting zero macroscopic magnetization. Considerable efforts have been devoted to the search for this novel material, from which we may get useful hints for prospective material exploration.

Human readers or radiologists routinely perform full-body multi-organ multi-disease detection and diagnosis in clinical practice, while most medical AI systems are built to focus on single organs with a narrow list of a few diseases. This might severely limit AI's clinical adoption. A certain number of AI models need to be assembled non-trivially to match the diagnostic process of a human reading a CT scan. In this paper, we construct a Unified Tumor Transformer (UniT) model to detect (tumor existence and location) and diagnose (tumor characteristics) eight major cancer-prevalent organs in CT scans. UniT is a query-based Mask Transformer model with the output of multi-organ and multi-tumor semantic segmentation. We decouple the object queries into organ queries, detection queries and diagnosis queries, and further establish hierarchical relationships among the three groups. This clinically-inspired architecture effectively assists inter- and intra-organ representation learning of tumors and facilitates the resolution of these complex, anatomically related multi-organ cancer image reading tasks. UniT is trained end-to-end using a curated large-scale CT images of 10,042 patients including eight major types of cancers and occurring non-cancer tumors (all are pathology-confirmed with 3D tumor masks annotated by radiologists). On the test set of 631 patients, UniT has demonstrated strong performance under a set of clinically relevant evaluation metrics, substantially outperforming both multi-organ segmentation methods and an assembly of eight single-organ expert models in tumor detection, segmentation, and diagnosis. Such a unified multi-cancer image reading model (UniT) can significantly reduce the number of false positives produced by combined multi-system models. This moves one step closer towards a universal high-performance cancer screening tool.

The development of accurate and efficient machine learning models for predicting the structure and properties of molecular crystals has been hindered by the scarcity of publicly available datasets of structures with property labels. To address this challenge, we introduce the Open Molecular Crystals 2025 (OMC25) dataset, a collection of over 27 million molecular crystal structures containing 12 elements and up to 300 atoms in the unit cell. The dataset was generated from dispersion-inclusive density functional theory (DFT) relaxation trajectories of over 230,000 randomly generated molecular crystal structures of around 50,000 organic molecules. OMC25 comprises diverse chemical compounds capable of forming different intermolecular interactions and a wide range of crystal packing motifs. We provide detailed information on the dataset's construction, composition, structure, and properties. To demonstrate the quality and use cases of OMC25, we further trained and evaluated state-of-the-art open-source machine learning interatomic potentials. By making this dataset publicly available, we aim to accelerate the development of more accurate and efficient machine learning models for molecular crystals.

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

We point out that there are two different chiral spin liquid states on the triangular lattice and discuss the conducting states that are expected on doping them. These states labeled CS1 and CS2 are associated with two distinct topological orders with different edge states, although they both spontaneously break time reversal symmetry and exhibit the same quantized spin Hall conductance. While CSL1 is related to the Kalmeyer-Laughlin state, CSL2 is the ν=4 member of Kitaev's 16 fold way classification. Both states are described within the Abrikosov fermion representation of spins, and the effect of doping can be accessed by introducing charged holons. On doping CSL2, condensation of charged holons leads to a topological d+id superconductor. However on doping CSL1 , in sharp contrast , two different scenarios can arise: first, if holons condense, a chiral metal with doubled unit cell and finite Hall conductivity is obtained. However, in a second novel scenario, the internal magnetic flux adjusts with doping and holons form a bosonic integer quantum Hall (BIQH) state. Remarkably, the latter phase is identical to a d+id superconductor. In this case the Mott insulator to superconductor transition is associated with a bosonic variant of the integer quantum Hall plateau transition for the holon. We connect the above two scenarios to two recent numerical studies of doped chiral spin liquids on triangular lattice. Our work clarifies the complex relation between topological superconductors, chiral spin liquids and quantum criticality .

Precise cell classification is essential in biomedical diagnostics and therapeutic monitoring, particularly for identifying diverse cell types involved in various diseases. Traditional cell classification methods such as flow cytometry depend on molecular labeling which is often costly, time-intensive, and can alter cell integrity. To overcome these limitations, we present a label-free machine learning framework for cell classification, designed for real-time sorting applications using bright-field microscopy images. This approach leverages a teacher-student model architecture enhanced by knowledge distillation, achieving high efficiency and scalability across different cell types. Demonstrated through a use case of classifying lymphocyte subsets, our framework accurately classifies T4, T8, and B cell types with a dataset of 80,000 preprocessed images, accessible via an open-source Python package for easy adaptation. Our teacher model attained 98\% accuracy in differentiating T4 cells from B cells and 93\% accuracy in zero-shot classification between T8 and B cells. Remarkably, our student model operates with only 0.02\% of the teacher model's parameters, enabling field-programmable gate array (FPGA) deployment. Our FPGA-accelerated student model achieves an ultra-low inference latency of just 14.5~μs and a complete cell detection-to-sorting trigger time of 24.7~μs, delivering 12x and 40x improvements over the previous state-of-the-art real-time cell analysis algorithm in inference and total latency, respectively, while preserving accuracy comparable to the teacher model. This framework provides a scalable, cost-effective solution for lymphocyte classification, as well as a new SOTA real-time cell sorting implementation for rapid identification of subsets using in situ deep learning on off-the-shelf computing hardware.

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.

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

We characterise the dynamics of neuronal activity, in terms of field theory, using neural units placed on a 2D-lattice modelling the cortical surface. The electrical activity of neuronal units was analysed with the aim of deriving a neural field model with a simple functional form that still able to predict or reproduce empirical findings. Each neural unit was modelled using a neural mass and the accompanying field theory was derived in the continuum limit. The field theory comprised coupled (real) Klein-Gordon fields, where predictions of the model fall within the range of experimental findings. These predictions included the frequency spectrum of electric activity measured from the cortex, which was derived using an equipartition of energy over eigenfunctions of the neural fields. Moreover, the neural field model was invariant, within a set of parameters, to the dynamical system used to model each neuronal mass. Specifically, topologically equivalent dynamical systems resulted in the same neural field model when connected in a lattice; indicating that the fields derived could be read as a canonical cortical field theory. We specifically investigated non-dispersive fields that provide a structure for the coding (or representation) of afferent information. Further elaboration of the ensuing neural field theory, including the effect of dispersive forces, could be of importance in the understanding of the cortical processing of information.

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.

Computational pathology relies on effective representation learning to support cancer research and precision medicine. Although self-supervised learning has driven major progress at the patch and whole-slide image levels, representation learning at the single-cell level remains comparatively underexplored, despite its importance for characterizing cell types and cellular phenotypes. We introduce LEMON (Learning Embeddings from Morphology Of Nuclei), a self-supervised foundation model for scalable single-cell image representation learning. Trained on millions of cell images from diverse tissues and cancer types, LEMON learns robust and versatile morphological representations that support large-scale single-cell analyses in pathology. We evaluate LEMON on five benchmark datasets across a range of prediction tasks and show that it provides strong performance, highlighting its potential as a new paradigm for cell-level computational pathology. Model weights are available at https://huggingface.co/aliceblondel/LEMON.

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.

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.

We present unit scaling, a paradigm for designing deep learning models that simplifies the use of low-precision number formats. Training in FP16 or the recently proposed FP8 formats offers substantial efficiency gains, but can lack sufficient range for out-of-the-box training. Unit scaling addresses this by introducing a principled approach to model numerics: seeking unit variance of all weights, activations and gradients at initialisation. Unlike alternative methods, this approach neither requires multiple training runs to find a suitable scale nor has significant computational overhead. We demonstrate the efficacy of unit scaling across a range of models and optimisers. We further show that existing models can be adapted to be unit-scaled, training BERT-Large in FP16 and then FP8 with no degradation in accuracy.