Daily Papers

Visual navigation in cluttered environments requires robots to recover previously observed structure and infer obstacles and free space that remain occluded. We present a framework that combines temporal aggregation and occupancy completion in an evidential bird's-eye-view (BEV) representation predicted from short RGB sequences. A decoder adapts frozen VGGT-Omega features and combines historical residual proposals using cellwise weights and a learned no-update option. The BEV predictor produces a local map in the latest ego frame without depth or camera-pose inputs or explicit geometric warping. The evidential model treats observed free space separately and predicts occupancy with associated confidence across the remaining supported region. We train the predictor on simulated RGB sequences paired with complete and visibility-masked occupancy annotations. Our experiments evaluate navigation in simulation and on a wheeled robot, with additional demonstrations on quadruped and humanoid robots. In simulated sequential two-goal navigation, our system achieves 86.3% success, outperforming the strongest evaluated baseline by 32.2 percentage points. Across 60 wheeled-robot trials in 20 scenes, it achieves 73.3% success, compared with 33.3% for the strongest evaluated baseline.

Virtual-cell models aim to predict how cell populations respond to perturbations, but control and treated cells are measured as unpaired populations, complicating the learning of perturbation-specific effects. We present SCALE, a conditional transport model that represents cells as unordered sets and predicts treated populations without cell-level matching. A shared set-aware encoder and conditional DiT backbone learn latent transport, making endpoint supervision directly delta-aligned without an auxiliary delta objective. Across genetic, chemical, developmental and immune perturbations, SCALE recovered gene-expression changes, response directions and population structure. In CRISPR data with dominant cell-line effects, SCALE outperformed competing methods across seven metrics and maintained separation among gene-target representations rather than collapsing them into a shared region. SCALE further prioritized cytokines predicted to produce distinct immune activation and inflammatory responses. Experiments using matched PBMC samples from three donors confirmed these predicted differences. Together, SCALE enables perturbation-specific prediction from unpaired populations and supports experimental prioritization.

Predicting single-cell perturbation responses requires mapping between two unpaired populations of cells measured before and after the perturbation. Optimal transport (OT) provides a principled framework for constructing such mappings by minimizing the transport cost, and neural OT methods (e.g., CellOT) have been employed for this prediction task. However, these methods rely on a fixed transport cost, typically the squared Euclidean distance. This cost may connect cells with the wrong responses. Lineage tracing provides the information needed to learn the cost, as heritable barcodes link the cells of the same clone before and after the perturbation. Here, we propose \CloneOT, a neural inverse OT method that learns both the transport cost and the transport map from partially lineage-traced single-cell datasets. \CloneOT\ represents the cost as a neural network. It learns the cost by minimizing the extra cost that the lineage adds to the optimal transport, so that the cheapest transport keeps the cells of each clone together. Our experiments demonstrate that \CloneOT\ recovers the correct transport on 2D datasets, while the squared Euclidean cost fails. Moreover, \CloneOT\ outperforms five baselines on 14 lineage-tracing perturbation scenarios of cancer cells, for both seen and unseen clones. Furthermore, we show that \CloneOT\ reveals the clone-specific transcriptional programs of drug-tolerant persister cells and forecasts the fate of each clone from its cells before treatment. Our implementation is available at https://github.com/poseidonchan/CloneOT.

Predicting cellular responses to perturbations supports the study of gene function, disease mechanisms, and therapeutic strategies. Despite advances in single-cell perturbation modeling, existing models typically optimize surrogate losses that do not directly reflect the biological criteria used for evaluation, so better data fitting need not yield better biological predictions. To address this mismatch, we introduce CellRFT, a reinforcement fine-tuning framework that uses biological evaluation as direct training feedback. CellRFT uses policy-gradient optimization to learn from non-differentiable evaluations of generated cell populations and integrates multiple biological rewards through hierarchical reward aggregation. Comprehensive experiments demonstrate CellRFT's applicability across different pretrained models and effectiveness in improving perturbation prediction, reveal that optimizing one biological criterion can help or hinder others, and show that complementary rewards can improve criteria beyond those directly optimized, offering a way to probe how biological metrics shape model behavior, with the potential to inform evaluation design. Code will be made available.

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

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.

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 Language Models (LLMs) suffer from huge number of parameters, which restricts their deployment on edge devices. Weight sharing is one promising solution that encourages weight reuse, effectively reducing memory usage with less performance drop. However, current weight sharing techniques primarily focus on small-scale models like BERT and employ coarse-grained sharing rules, e.g., layer-wise. This becomes limiting given the prevalence of LLMs and sharing an entire layer or block obviously diminishes the flexibility of weight sharing. In this paper, we present a perspective on $textbf{head-wise shareable attention for large language models}. We further propose two memory-efficient methods that share parameters across attention heads, with a specific focus on LLMs. Both of them use the same dynamic strategy to select the shared weight matrices. The first method directly reuses the pre-trained weights without retraining, denoted as DirectShare. The second method first post-trains with constraint on weight matrix similarity and then shares, denoted as PostShare$. Experimental results reveal our head-wise shared models still maintain satisfactory capabilities, demonstrating the feasibility of fine-grained weight sharing applied to LLMs.

Learning the response of single-cells to various treatments offers great potential to enable targeted therapies. In this context, neural optimal transport (OT) has emerged as a principled methodological framework because it inherently accommodates the challenges of unpaired data induced by cell destruction during data acquisition. However, most existing OT approaches are incapable of conditioning on different treatment contexts (e.g., time, drug treatment, drug dosage, or cell type) and we still lack methods that unanimously show promising generalization performance to unseen treatments. Here, we propose the Conditional Monge Gap which learns OT maps conditionally on arbitrary covariates. We demonstrate its value in predicting single-cell perturbation responses conditional to one or multiple drugs, a drug dosage, or combinations thereof. We find that our conditional models achieve results comparable and sometimes even superior to the condition-specific state-of-the-art on scRNA-seq as well as multiplexed protein imaging data. Notably, by aggregating data across conditions we perform cross-task learning which unlocks remarkable generalization abilities to unseen drugs or drug dosages, widely outperforming other conditional models in capturing heterogeneity (i.e., higher moments) in the perturbed population. Finally, by scaling to hundreds of conditions and testing on unseen drugs, we narrow the gap between structure-based and effect-based drug representations, suggesting a promising path to the successful prediction of perturbation effects for unseen treatments.

Deep Neural Networks (DNN) have achieved state-of-the-art results in a wide range of tasks, with the best results obtained with large training sets and large models. In the past, GPUs enabled these breakthroughs because of their greater computational speed. In the future, faster computation at both training and test time is likely to be crucial for further progress and for consumer applications on low-power devices. As a result, there is much interest in research and development of dedicated hardware for Deep Learning (DL). Binary weights, i.e., weights which are constrained to only two possible values (e.g. -1 or 1), would bring great benefits to specialized DL hardware by replacing many multiply-accumulate operations by simple accumulations, as multipliers are the most space and power-hungry components of the digital implementation of neural networks. We introduce BinaryConnect, a method which consists in training a DNN with binary weights during the forward and backward propagations, while retaining precision of the stored weights in which gradients are accumulated. Like other dropout schemes, we show that BinaryConnect acts as regularizer and we obtain near state-of-the-art results with BinaryConnect on the permutation-invariant MNIST, CIFAR-10 and SVHN.

The retina offers a noninvasive window into neurodegenerative disease, capturing subtle structural patterns associated with a risk of future cognitive decline. Vision-language alignment frameworks such as REVEAL have shown that pairing retinal fundus images with structured clinical risk narratives improves early prediction of Alzheimer's disease (AD). A key design choice in these approaches is the use of phenotypic grouping, where individuals with similar risk profiles are treated as multi-positive pairs during contrastive learning. However, existing methods operationalize phenotypic similarity as a discrete construct, relying on hard group assignments that impose rigid supervision and decouple group formation from representation learning. We propose a continuous formulation of phenotypic structure within contrastive learning. Rather than assigning samples to fixed clusters, we model inter-subject similarity as a differentiable weighting function derived from intra-modality embedding similarities in both retinal images and risk profiles. These weights define soft multi-positive relationships through a continuous aggregation operator, enabling graded supervision that reflects the spectrum nature of disease risk. We further introduce a soft-target contrastive objective that jointly learns cross-modal alignment and phenotypic structure in an end-to-end manner. Evaluated on UK Biobank retinal imaging data for incident AD prediction, the proposed framework consistently outperforms discrete group-based contrastive learning and standard vision-language baselines. By treating phenotypic similarity as a learnable, continuous signal rather than a fixed grouping rule, our approach provides a principled and robust foundation for population-scale neurodegenerative risk modeling from multi-modal retinal and clinical data.

Weight sharing is a fundamental concept in neural architecture search (NAS), enabling gradient-based methods to explore cell-based architecture spaces significantly faster than traditional blackbox approaches. In parallel, weight entanglement has emerged as a technique for intricate parameter sharing among architectures within macro-level search spaces. %However, the macro structure of such spaces poses compatibility challenges for gradient-based NAS methods. %As a result, blackbox optimization methods have been commonly employed, particularly in conjunction with supernet training, to maintain search efficiency. %Due to the inherent differences in the structure of these search spaces, these Since weight-entanglement poses compatibility challenges for gradient-based NAS methods, these two paradigms have largely developed independently in parallel sub-communities. This paper aims to bridge the gap between these sub-communities by proposing a novel scheme to adapt gradient-based methods for weight-entangled spaces. This enables us to conduct an in-depth comparative assessment and analysis of the performance of gradient-based NAS in weight-entangled search spaces. Our findings reveal that this integration of weight-entanglement and gradient-based NAS brings forth the various benefits of gradient-based methods (enhanced performance, improved supernet training properties and superior any-time performance), while preserving the memory efficiency of weight-entangled spaces. The code for our work is openly accessible https://anonymous.4open.science/r/TangleNAS-527C{here}

In theoretical neuroscience, recent work leverages deep learning tools to explore how some network attributes critically influence its learning dynamics. Notably, initial weight distributions with small (resp. large) variance may yield a rich (resp. lazy) regime, where significant (resp. minor) changes to network states and representation are observed over the course of learning. However, in biology, neural circuit connectivity could exhibit a low-rank structure and therefore differs markedly from the random initializations generally used for these studies. As such, here we investigate how the structure of the initial weights -- in particular their effective rank -- influences the network learning regime. Through both empirical and theoretical analyses, we discover that high-rank initializations typically yield smaller network changes indicative of lazier learning, a finding we also confirm with experimentally-driven initial connectivity in recurrent neural networks. Conversely, low-rank initialization biases learning towards richer learning. Importantly, however, as an exception to this rule, we find lazier learning can still occur with a low-rank initialization that aligns with task and data statistics. Our research highlights the pivotal role of initial weight structures in shaping learning regimes, with implications for metabolic costs of plasticity and risks of catastrophic forgetting.

Adapting a pre-trained foundation model on downstream tasks should ensure robustness against distribution shifts without the need to retrain the whole model. Although existing weight interpolation methods are simple yet effective, we argue their static nature limits downstream performance while achieving efficiency. In this work, we propose DaWin, a training-free dynamic weight interpolation method that leverages the entropy of individual models over each unlabeled test sample to assess model expertise, and compute per-sample interpolation coefficients dynamically. Unlike previous works that typically rely on additional training to learn such coefficients, our approach requires no training. Then, we propose a mixture modeling approach that greatly reduces inference overhead raised by dynamic interpolation. We validate DaWin on the large-scale visual recognition benchmarks, spanning 14 tasks across robust fine-tuning -- ImageNet and derived five distribution shift benchmarks -- and multi-task learning with eight classification tasks. Results demonstrate that DaWin achieves significant performance gain in considered settings, with minimal computational overhead. We further discuss DaWin's analytic behavior to explain its empirical success.

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

A growing literature in computational neuroscience leverages gradient descent and learning algorithms that approximate it to study synaptic plasticity in the brain. However, the vast majority of this work ignores a critical underlying assumption: the choice of distance for synaptic changes - i.e. the geometry of synaptic plasticity. Gradient descent assumes that the distance is Euclidean, but many other distances are possible, and there is no reason that biology necessarily uses Euclidean geometry. Here, using the theoretical tools provided by mirror descent, we show that the distribution of synaptic weights will depend on the geometry of synaptic plasticity. We use these results to show that experimentally-observed log-normal weight distributions found in several brain areas are not consistent with standard gradient descent (i.e. a Euclidean geometry), but rather with non-Euclidean distances. Finally, we show that it should be possible to experimentally test for different synaptic geometries by comparing synaptic weight distributions before and after learning. Overall, our work shows that the current paradigm in theoretical work on synaptic plasticity that assumes Euclidean synaptic geometry may be misguided and that it should be possible to experimentally determine the true geometry of synaptic plasticity in the brain.

In federated learning (FL), weighted aggregation of local models is conducted to generate a global model, and the aggregation weights are normalized (the sum of weights is 1) and proportional to the local data sizes. In this paper, we revisit the weighted aggregation process and gain new insights into the training dynamics of FL. First, we find that the sum of weights can be smaller than 1, causing global weight shrinking effect (analogous to weight decay) and improving generalization. We explore how the optimal shrinking factor is affected by clients' data heterogeneity and local epochs. Second, we dive into the relative aggregation weights among clients to depict the clients' importance. We develop client coherence to study the learning dynamics and find a critical point that exists. Before entering the critical point, more coherent clients play more essential roles in generalization. Based on the above insights, we propose an effective method for Federated Learning with Learnable Aggregation Weights, named as FedLAW. Extensive experiments verify that our method can improve the generalization of the global model by a large margin on different datasets and models.

Modern neural network training relies on optimizers such as Adam and Muon which act on each weight matrix as a single object. Yet every weight matrix carries two distinct quantities -- a magnitude and a direction -- and all optimizers stepping in the matrix as a whole couple their dynamics: the directional change from an update depends on the current magnitude, while the magnitude drifts as a byproduct of learning the direction, so neither is governed directly by the learning rate. Typical training therefore leans on surrounding recipes such as weight decay and warmup to keep learning stable at scale, though these regulate the coupling only indirectly; other recent methods instead constrain the weight to a fixed-norm sphere, but add no learnable magnitude, leaving scale control to normalization layers alone. We propose Magnitude--Direction (MD) Decoupling, an optimizer modification that factorizes each weight into a fixed-norm direction on a hypersphere and learnable per-row and per-column magnitude gains, updated at separate learning rates, all while the model still sees a single fused weight tensor. The method is agnostic to the base optimizer and removes the need for weight decay and warmup. Across both Adam and Muon, MD Decoupling improves on well-tuned baselines, transfers the optimal LR across model width without retuning, and continues to help at scale on large Mixture-of-Experts (MoE) models. Treating magnitude and direction as separately controlled quantities thus yields more predictable training dynamics and a simple, broadly applicable improvement to modern optimizers.

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.

Quantile regression is a fundamental problem in statistical learning motivated by a need to quantify uncertainty in predictions, or to model a diverse population without being overly reductive. For instance, epidemiological forecasts, cost estimates, and revenue predictions all benefit from being able to quantify the range of possible values accurately. As such, many models have been developed for this problem over many years of research in statistics, machine learning, and related fields. Rather than proposing yet another (new) algorithm for quantile regression we adopt a meta viewpoint: we investigate methods for aggregating any number of conditional quantile models, in order to improve accuracy and robustness. We consider weighted ensembles where weights may vary over not only individual models, but also over quantile levels, and feature values. All of the models we consider in this paper can be fit using modern deep learning toolkits, and hence are widely accessible (from an implementation point of view) and scalable. To improve the accuracy of the predicted quantiles (or equivalently, prediction intervals), we develop tools for ensuring that quantiles remain monotonically ordered, and apply conformal calibration methods. These can be used without any modification of the original library of base models. We also review some basic theory surrounding quantile aggregation and related scoring rules, and contribute a few new results to this literature (for example, the fact that post sorting or post isotonic regression can only improve the weighted interval score). Finally, we provide an extensive suite of empirical comparisons across 34 data sets from two different benchmark repositories.

We present a novel type of neural fields that uses general radial bases for signal representation. State-of-the-art neural fields typically rely on grid-based representations for storing local neural features and N-dimensional linear kernels for interpolating features at continuous query points. The spatial positions of their neural features are fixed on grid nodes and cannot well adapt to target signals. Our method instead builds upon general radial bases with flexible kernel position and shape, which have higher spatial adaptivity and can more closely fit target signals. To further improve the channel-wise capacity of radial basis functions, we propose to compose them with multi-frequency sinusoid functions. This technique extends a radial basis to multiple Fourier radial bases of different frequency bands without requiring extra parameters, facilitating the representation of details. Moreover, by marrying adaptive radial bases with grid-based ones, our hybrid combination inherits both adaptivity and interpolation smoothness. We carefully designed weighting schemes to let radial bases adapt to different types of signals effectively. Our experiments on 2D image and 3D signed distance field representation demonstrate the higher accuracy and compactness of our method than prior arts. When applied to neural radiance field reconstruction, our method achieves state-of-the-art rendering quality, with small model size and comparable training speed.

Weight oscillation is an undesirable side effect of quantization-aware training, in which quantized weights frequently jump between two quantized levels, resulting in training instability and a sub-optimal final model. We discover that the learnable scaling factor, a widely-used de facto setting in quantization aggravates weight oscillation. In this study, we investigate the connection between the learnable scaling factor and quantized weight oscillation and use ViT as a case driver to illustrate the findings and remedies. In addition, we also found that the interdependence between quantized weights in query and key of a self-attention layer makes ViT vulnerable to oscillation. We, therefore, propose three techniques accordingly: statistical weight quantization (rm StatsQ) to improve quantization robustness compared to the prevalent learnable-scale-based method; confidence-guided annealing (rm CGA) that freezes the weights with high confidence and calms the oscillating weights; and query-key reparameterization (rm QKR) to resolve the query-key intertwined oscillation and mitigate the resulting gradient misestimation. Extensive experiments demonstrate that these proposed techniques successfully abate weight oscillation and consistently achieve substantial accuracy improvement on ImageNet. Specifically, our 2-bit DeiT-T/DeiT-S algorithms outperform the previous state-of-the-art by 9.8% and 7.7%, respectively. Code and models are available at: https://github.com/nbasyl/OFQ.

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

White blood cell (WBC) classification is fundamental for hematology applications such as infection assessment, leukemia screening, and treatment monitoring. However, real-world WBC datasets present substantial appearance variations caused by staining and scanning conditions, as well as severe class imbalance in which common cell types dominate while rare but clinically important categories are underrepresented. To address these challenges, we propose a stain-normalized, decoupled training framework that first learns transferable representations using instance-balanced sampling, and then rebalances the classifier with class-aware sampling and a hybrid loss combining effective-number weighting and focal modulation. In inference stage, we further enhance robustness by ensembling various trained backbones with test-time augmentation. Our approach achieved the top rank on the leaderboard of the WBCBench 2026: Robust White Blood Cell Classification Challenge at ISBI 2026.

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

The pre-training cost of large language models (LLMs) is prohibitive. One cutting-edge approach to reduce the cost is zero-shot weight transfer, also known as model growth for some cases, which magically transfers the weights trained in a small model to a large model. However, there are still some theoretical mysteries behind the weight transfer. In this paper, inspired by prior applications of mean field theory to neural network dynamics, we introduce a mean field ansatz to provide a theoretical explanation for weight transfer. Specifically, we propose the row-column (RC) ansatz under the mean field point of view, which describes the measure structure of the weights in the neural network (NN) and admits a close measure dynamic. Thus, the weights of different sizes NN admit a common distribution under proper assumptions, and weight transfer methods can be viewed as sampling methods. We empirically validate the RC ansatz by exploring simple MLP examples and LLMs such as GPT-3 and Llama-3.1. We show the mean-field point of view is adequate under suitable assumptions which can provide theoretical support for zero-shot weight transfer.

Single cell segmentation is critical and challenging in live cell imaging data analysis. Traditional image processing methods and tools require time-consuming and labor-intensive efforts of manually fine-tuning parameters. Slight variations of image setting may lead to poor segmentation results. Recent development of deep convolutional neural networks(CNN) provides a potentially efficient, general and robust method for segmentation. Most existing CNN-based methods treat segmentation as a pixel-wise classification problem. However, three unique problems of cell images adversely affect segmentation accuracy: lack of established training dataset, few pixels on cell boundaries, and ubiquitous blurry features. The problem becomes especially severe with densely packed cells, where a pixel-wise classification method tends to identify two neighboring cells with blurry shared boundary as one cell, leading to poor cell count accuracy and affecting subsequent analysis. Here we developed a different learning strategy that combines strengths of CNN and watershed algorithm. The method first trains a CNN to learn Euclidean distance transform of binary masks corresponding to the input images. Then another CNN is trained to detect individual cells in the Euclidean distance transform. In the third step, the watershed algorithm takes the outputs from the previous steps as inputs and performs the segmentation. We tested the combined method and various forms of the pixel-wise classification algorithm on segmenting fluorescence and transmitted light images. The new method achieves similar pixel accuracy but significant higher cell count accuracy than pixel-wise classification methods do, and the advantage is most obvious when applying on noisy images of densely packed cells.

We introduce TWIG (Tree-structured Weights with Inherited Gates), a representation in which every weight of a neural network is the end of a path of small discrete decisions: a sign, a shift by a power of two, a zero gate, an index into a shared table. Weights that belong together share the upper part of their paths, and each decision is inherited by every weight below it, so it is stored once and applied once. This simple change has three consequences. Any trained network can be written as a TWIG, and when the decisions are powers of two its weight layers become circuits made almost entirely of wires and adders, suited to chips whose weights are fixed at fabrication. Pruning, quantization, low-rank factorization, codebooks and weight sharing become edits of one object, so a single optimizer can choose among all of them for a whole network. And choosing the decisions is the ground-state problem of a higher-order Boltzmann machine whose interactions follow the paths of the tree, the problem class that annealers and quantum optimizers are built to solve. Today these questions are handled apart: each compression method brings its own format and solver, a circuit with fixed weights needs a dedicated constant multiplier for every weight, and discrete solvers reach only narrow subproblems such as rounding. Weight formats have long been moving toward shared decisions, through group scales, shared exponents, microexponents and sparse weights; TWIG takes this trend to its end, and every common format is a shallow TWIG at no extra cost. On five weight matrices of a large language model, a flat tree whose signed power-of-two terms are chosen per weight for circuit cost, with no group scales, needs 9--15\% fewer additions than GPTQ at equal layer error at 3- and 4-bit accuracy on typical matrices, and 20--55\% fewer on matrices with strong outliers.

Traditional weight of evidence assigns a credit characteristic a value based on its association with default across a population. Credit analysis also requires an assessment of that characteristic in the context of an individual applicant's record. We study conditional weight of evidence for this purpose. It measures the change in default log odds from observing a characteristic after the remaining credit information is known. Its sign identifies whether the characteristic adds adverse or favorable information for that applicant, and its magnitude measures the strength of that information. The same characteristic value can therefore receive different assessments for applicants with different payment histories or other credit attributes. We develop estimators using gradient-boosted trees and evaluate their accuracy in a bureau-style simulation. Regressions of the full model's predicted probabilities recover conditional evidence more accurately than separate models fitted to default outcomes, provided the full model is accurate. They also recover a deliberately constructed file-age effect whose direction varies with utilization and is often missed by marginal weight of evidence. Local class-frequency estimates improve on marginal weight of evidence but remain inaccurate for some weak effects. An application to FICO HELOC data illustrates estimation when the population evidence is unknown. Conditional weight of evidence provides an applicant-specific interpretation of the information in a credit characteristic; its population summary, a conditional information value, splits the joint information in the record across blocks when averaged over orderings. Neither is an adverse action reason, which explains the fitted score difference between the applicant and chosen passing records.

Natural intelligences (NIs) thrive in a dynamic world - they learn quickly, sometimes with only a few samples. In contrast, artificial intelligences (AIs) typically learn with a prohibitive number of training samples and computational power. What design principle difference between NI and AI could contribute to such a discrepancy? Here, we investigate the role of weight polarity: development processes initialize NIs with advantageous polarity configurations; as NIs grow and learn, synapse magnitudes update, yet polarities are largely kept unchanged. We demonstrate with simulation and image classification tasks that if weight polarities are adequately set a priori, then networks learn with less time and data. We also explicitly illustrate situations in which a priori setting the weight polarities is disadvantageous for networks. Our work illustrates the value of weight polarities from the perspective of statistical and computational efficiency during learning.

How the wiring and functional organization of cortex shape recurrent computation remains a central question in both neuroscience and machine learning. Here, we leverage data released through the Machine Intelligence from Cortical Networks (MICrONS) program--a functional connectomics resource spanning multiple areas of mouse visual cortex, in which dense calcium imaging is co-registered with high-resolution electron microscopy reconstruction from the same animal--to build biologically grounded recurrent neural networks. Using neuronal spatial coordinates, anatomical connectivity, and function-derived relationships from nearly 12,000 coregistered excitatory neurons, we initialize recurrent weights and impose communication-aware spatial constraints during learning. Across three cognitive decision-making tasks, networks constrained by cortical structure and function consistently outperform baseline and partially constrained models. Functional weight initialization provides the largest gain, while real spatial embedding yields robust additional improvements across conditions. These biologically grounded networks also develop low-entropy, modular, and small-world organization, and retain strong performance even when recurrence is restricted to positive weights. Together, our results show that the machinery of cortex--its geometry, wiring, and functional structure--can be harnessed as a powerful inductive basis for building recurrent networks that learn more effectively while converging toward key organizational principles of biological computation.

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.

It is increasingly common to encounter data from dynamic processes captured by static cross-sectional measurements over time, particularly in biomedical settings. Recent attempts to model individual trajectories from this data use optimal transport to create pairwise matchings between time points. However, these methods cannot model continuous dynamics and non-linear paths that entities can take in these systems. To address this issue, we establish a link between continuous normalizing flows and dynamic optimal transport, that allows us to model the expected paths of points over time. Continuous normalizing flows are generally under constrained, as they are allowed to take an arbitrary path from the source to the target distribution. We present TrajectoryNet, which controls the continuous paths taken between distributions to produce dynamic optimal transport. We show how this is particularly applicable for studying cellular dynamics in data from single-cell RNA sequencing (scRNA-seq) technologies, and that TrajectoryNet improves upon recently proposed static optimal transport-based models that can be used for interpolating cellular distributions.

Earlier diagnosis of Leukemia can save thousands of lives annually. The prognosis of leukemia is challenging without the morphological information of White Blood Cells (WBC) and relies on the accessibility of expensive microscopes and the availability of hematologists to analyze Peripheral Blood Samples (PBS). Deep Learning based methods can be employed to assist hematologists. However, these algorithms require a large amount of labeled data, which is not readily available. To overcome this limitation, we have acquired a realistic, generalized, and large dataset. To collect this comprehensive dataset for real-world applications, two microscopes from two different cost spectrums (high-cost HCM and low-cost LCM) are used for dataset capturing at three magnifications (100x, 40x, 10x) through different sensors (high-end camera for HCM, middle-level camera for LCM and mobile-phone camera for both). The high-sensor camera is 47 times more expensive than the middle-level camera and HCM is 17 times more expensive than LCM. In this collection, using HCM at high resolution (100x), experienced hematologists annotated 10.3k WBC types (14) and artifacts, having 55k morphological labels (Cell Size, Nuclear Chromatin, Nuclear Shape, etc.) from 2.4k images of several PBS leukemia patients. Later on, these annotations are transferred to other 2 magnifications of HCM, and 3 magnifications of LCM, and on each camera captured images. Along with the LeukemiaAttri dataset, we provide baselines over multiple object detectors and Unsupervised Domain Adaptation (UDA) strategies, along with morphological information-based attribute prediction. The dataset will be publicly available after publication to facilitate the research in this direction.

Nucleus segmentation is a challenging task due to the crowded distribution and blurry boundaries of nuclei. Recent approaches represent nuclei by means of polygons to differentiate between touching and overlapping nuclei and have accordingly achieved promising performance. Each polygon is represented by a set of centroid-to-boundary distances, which are in turn predicted by features of the centroid pixel for a single nucleus. However, using the centroid pixel alone does not provide sufficient contextual information for robust prediction and thus degrades the segmentation accuracy. To handle this problem, we propose a Context-aware Polygon Proposal Network (CPP-Net) for nucleus segmentation. First, we sample a point set rather than one single pixel within each cell for distance prediction. This strategy substantially enhances contextual information and thereby improves the robustness of the prediction. Second, we propose a Confidence-based Weighting Module, which adaptively fuses the predictions from the sampled point set. Third, we introduce a novel Shape-Aware Perceptual (SAP) loss that constrains the shape of the predicted polygons. Here, the SAP loss is based on an additional network that is pre-trained by means of mapping the centroid probability map and the pixel-to-boundary distance maps to a different nucleus representation. Extensive experiments justify the effectiveness of each component in the proposed CPP-Net. Finally, CPP-Net is found to achieve state-of-the-art performance on three publicly available databases, namely DSB2018, BBBC06, and PanNuke. Code of this paper is available at \url{https://github.com/csccsccsccsc/cpp-net

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

Let T be a rooted and weighted tree, where the weight of any node is equal to the sum of the weights of its children. The popular Treemap algorithm visualizes such a tree as a hierarchical partition of a square into rectangles, where the area of the rectangle corresponding to any node in T is equal to the weight of that node. The aspect ratio of the rectangles in such a rectangular partition necessarily depends on the weights and can become arbitrarily high. We introduce a new hierarchical partition scheme, called a polygonal partition, which uses convex polygons rather than just rectangles. We present two methods for constructing polygonal partitions, both having guarantees on the worst-case aspect ratio of the constructed polygons; in particular, both methods guarantee a bound on the aspect ratio that is independent of the weights of the nodes. We also consider rectangular partitions with slack, where the areas of the rectangles may differ slightly from the weights of the corresponding nodes. We show that this makes it possible to obtain partitions with constant aspect ratio. This result generalizes to hyper-rectangular partitions in R^d. We use these partitions with slack for embedding ultrametrics into d-dimensional Euclidean space: we give a rm polylog(Delta)-approximation algorithm for embedding n-point ultrametrics into R^d with minimum distortion, where Delta denotes the spread of the metric, i.e., the ratio between the largest and the smallest distance between two points. The previously best-known approximation ratio for this problem was polynomial in n. This is the first algorithm for embedding a non-trivial family of weighted-graph metrics into a space of constant dimension that achieves polylogarithmic approximation ratio.

Dense retrieval powers retrieval-augmented generation, semantic search, and question answering, yet the theoretical basis for choosing between shared and dual query-document projections remains unclear. We introduce a bias-variance theory for low-rank bilinear scoring. Shared projections induce positive-semidefinite operators, whereas dual projections realize arbitrary low-rank operators. We derive their exact approximation gap and prove a local Gaussian boundary: dual has lower risk exactly when squared directional signal exceeds the estimation cost of its additional degrees of freedom. This boundary motivates the Cross-fitted Asymmetry Risk Selector (CARS), which estimates reproducible directional signal from training pairs; its Gaussian counterpart admits exact selection-power and regret formulas. Guided by the theory, we run retrieval experiments across multiple datasets and embedding models. The mean Dual-minus-Shared NDCG@10 advantage more than doubles as query rotation increases from 0 degrees to 90 degrees. In the rank-sample-size grids, Shared wins 13 of 16 cells at n=32, whereas Dual wins all 32 cells at n=1024 and n=2048. Consistent with this shift, all 168 comparable operator-risk curves move toward Dual as training data grow. Compared to the two fixed-geometry baselines, CARS reduces held-out regret by 49-96% and achieves 90.1% mean geometry-selection accuracy.

Decentralized learning often involves a weighted global loss with heterogeneous node weights λ. We revisit two natural strategies for incorporating these weights: (i) embedding them into the local losses to retain a uniform weight (and thus a doubly stochastic matrix), and (ii) keeping the original losses while employing a λ-induced row-stochastic matrix. Although prior work shows that both strategies target the same λ-weighted global loss, it remains unclear whether the Euclidean-space guarantees are tight and what fundamentally differentiates their behaviors. To clarify this, we develop a weighted Hilbert-space framework L^2(λ;R^d) and obtain convergence rates that are strictly tighter than those from standard Euclidean analysis. In this geometry, the row-stochastic matrix becomes self-adjoint whereas the doubly stochastic one does not, creating additional penalty terms that amplify consensus error, thereby slowing convergence. Consequently, the difference in convergence arises not only from spectral gaps but also from these penalty terms. We then derive sufficient conditions under which the row-stochastic design converges faster even with a smaller spectral gap. Finally, by using a Rayleigh-quotient and Loewner-order eigenvalue comparison, we further obtain topology conditions that guarantee this advantage and yield practical topology-design guidelines.

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.

The modern deep learning field is a scale-centric one. Larger models have been shown to consistently perform better than smaller models of similar architecture. In many sub-domains of biomedical research, however, the model scaling is bottlenecked by the amount of available training data, and the high cost associated with generating and validating additional high quality data. Despite the practical hurdle, the majority of the ongoing research still focuses on building bigger foundation models, whereas the alternative of improving the ability of small models has been under-explored. Here we experiment with building models with 10-30M parameters, tiny by modern standards, to perform the single-cell segmentation task. An important design choice is the incorporation of a recursive structure into the model's forward computation graph, leading to a more parameter-efficient architecture. We found that for the single-cell segmentation, on multiple benchmarks, our small model, UCell, matches the performance of models 10-20 times its size, and with a similar generalizability to unseen out-of-domain data. More importantly, we found that ucell can be trained from scratch using only a set of microscopy imaging data, without relying on massive pretraining on natural images, and therefore decouples the model building from any external commercial interests. Finally, we examined and confirmed the adaptability of ucell by performing a wide range of one-shot and few-shot fine tuning experiments on a diverse set of small datasets. Implementation is available at https://github.com/jiyuuchc/ucell

We present a memory and computation efficient ternary weight networks (TWNs) - with weights constrained to +1, 0 and -1. The Euclidian distance between full (float or double) precision weights and the ternary weights along with a scaling factor is minimized in training stage. Besides, a threshold-based ternary function is optimized to get an approximated solution which can be fast and easily computed. TWNs have shown better expressive abilities than binary precision counterparts. Meanwhile, TWNs achieve up to 16times model compression rate and need fewer multiplications compared with the float32 precision counterparts. Extensive experiments on MNIST, CIFAR-10, and ImageNet datasets show that the TWNs achieve much better result than the Binary-Weight-Networks (BWNs) and the classification performance on MNIST and CIFAR-10 is very close to the full precision networks. We also verify our method on object detection task and show that TWNs significantly outperforms BWN by more than 10\% mAP on PASCAL VOC dataset. The pytorch version of source code is available at: https://github.com/Thinklab-SJTU/twns.

Computational pathology models infer biologically and clinically meaningful outcomes from histology, but their predictions are shaped by complex, intertwined tissue signals whose roles are important to understand. Common pixel- and feature-space perturbations can produce implausible tissue, making model responses difficult to interpret. We introduce CPathOGen, a conditional latent-diffusion framework for generating paired H\&E counterfactuals with explicit controls over cellular spatial organization, nuclear morphology, and stain appearance. Cellular maps condition spatial structure through a spatial encoder, while a morphology/appearance vector modulates denoising through blockwise feature-wise linear modulation (FiLM). On held-out H\&E tiles, CPathOGen generates visually plausible tissue with improved distributional agreement after spatially guided selection, as reflected by lower Fréchet Inception Distance (FID) and Kernel Inception Distance (KID); generated cells track requested abundance and position, and measured morphology and color vary monotonically with their controls. We use these verified interventions to probe pathology encoders with endpoint heads, task-specific classifiers, and survival models. Responses are quantified using total variation distance and prediction-flip rate. We further introduce the Biology-Nuisance Sensitivity Ratio, a metric that contrasts model sensitivity to biologically motivated morphology and spatial factors with sensitivity to non-biological, stain-related nuisance variation. CPathOGen provides a practical, fidelity-audited framework for evaluating robustness and controlled feature sensitivity in computational pathology model. https://github.com/a12dongithub/PathOGen{GitHub} and https://huggingface.co/a12donhf/CPathOGen{Hugging~Face}.

The weight matrix (WM) of a neural network (NN) is its program. The programs of many traditional NNs are learned through gradient descent in some error function, then remain fixed. The WM of a self-referential NN, however, can keep rapidly modifying all of itself during runtime. In principle, such NNs can meta-learn to learn, and meta-meta-learn to meta-learn to learn, and so on, in the sense of recursive self-improvement. While NN architectures potentially capable of implementing such behaviour have been proposed since the '90s, there have been few if any practical studies. Here we revisit such NNs, building upon recent successes of fast weight programmers and closely related linear Transformers. We propose a scalable self-referential WM (SRWM) that learns to use outer products and the delta update rule to modify itself. We evaluate our SRWM in supervised few-shot learning and in multi-task reinforcement learning with procedurally generated game environments. Our experiments demonstrate both practical applicability and competitive performance of the proposed SRWM. Our code is public.

Recent advances in artificial neural networks for machine learning, and language modeling in particular, have established a family of recurrent neural network (RNN) architectures that, unlike conventional RNNs with vector-form hidden states, use two-dimensional (2D) matrix-form hidden states. Such 2D-state RNNs, known as Fast Weight Programmers (FWPs), can be interpreted as a neural network whose synaptic weights (called fast weights) dynamically change over time as a function of input observations, and serve as short-term memory storage; corresponding synaptic weight modifications are controlled or programmed by another network (the programmer) whose parameters are trained (e.g., by gradient descent). In this Primer, we review the technical foundations of FWPs, their computational characteristics, and their connections to transformers and state space models. We also discuss connections between FWPs and models of synaptic plasticity in the brain, suggesting a convergence of natural and artificial intelligence.

Weighting methods in causal inference have been widely used to achieve a desirable level of covariate balancing. However, the existing weighting methods have desirable theoretical properties only when a certain model, either the propensity score or outcome regression model, is correctly specified. In addition, the corresponding estimators do not behave well for finite samples due to large variance even when the model is correctly specified. In this paper, we consider to use the integral probability metric (IPM), which is a metric between two probability measures, for covariate balancing. Optimal weights are determined so that weighted empirical distributions for the treated and control groups have the smallest IPM value for a given set of discriminators. We prove that the corresponding estimator can be consistent without correctly specifying any model (neither the propensity score nor the outcome regression model). In addition, we empirically show that our proposed method outperforms existing weighting methods with large margins for finite samples.

Training classifiers is difficult with severe class imbalance, but many rare events are the culmination of a sequence with much more common intermediate outcomes. For example, in online marketing a user first sees an ad, then may click on it, and finally may make a purchase; estimating the probability of purchases is difficult because of their rarity. We show both theoretically and through data experiments that the more abundant data in earlier steps may be leveraged to improve estimation of probabilities of rare events. We present PRESTO, a relaxation of the proportional odds model for ordinal regression. Instead of estimating weights for one separating hyperplane that is shifted by separate intercepts for each of the estimated Bayes decision boundaries between adjacent pairs of categorical responses, we estimate separate weights for each of these transitions. We impose an L1 penalty on the differences between weights for the same feature in adjacent weight vectors in order to shrink towards the proportional odds model. We prove that PRESTO consistently estimates the decision boundary weights under a sparsity assumption. Synthetic and real data experiments show that our method can estimate rare probabilities in this setting better than both logistic regression on the rare category, which fails to borrow strength from more abundant categories, and the proportional odds model, which is too inflexible.

Statistical data fusion combines two panels that share a block of covariates but observe disjoint outcome blocks, and in its traditional form no row observes both outcomes at once. That rules out the discriminative criterion one would rather train a Deep Boltzmann Machine with, since multi-prediction training needs ground truth for whatever it holds out. We propose observed-block multi-prediction, which restricts the multi-prediction objective to targets drawn from what each row actually observes. It is well defined for any missingness pattern and reduces to the original criterion when rows are complete. Having a discriminative criterion that survives the setting lets us ask whether the joint model is needed at all, by separating what it contributes into a representation part and an inference part. On two consumer panels, on grids over sample size and covariate width spanning 35 cells and 875 runs, the fine-tuned DBM is the best of fifteen methods in every cell; but almost none of that advantage comes from generative pre-training, which is confined to the smallest sample size on one dataset and absent on the other. It comes from conditioning on one outcome block when predicting the other. This term amounts to +0.19 and +0.07 percentage points, is positive in all 35 cells, and, unlike every other contribution we measure, neither decays as the panels grow, nor requires a second hidden layer, nor requires more inference. Permuting one outcome block to destroy its association with the other removes the gain entirely, which is what the account predicts. The margins are small. But a small effect that does not decay is a different object from one that does, because it rests on evidence that no model mapping covariates to outcomes can accept.

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.

The classification of white blood cells (WBCs) from peripheral blood smears is critical for the diagnosis of leukemia. However, automated approaches still struggle due to challenges including class imbalance, domain shift, and morphological continuum confusion, where adjacent maturation stages exhibit subtle, overlapping features. We present a multi-stage fine-tuning methodology for 13-class WBC classification in the WBCBench 2026 Challenge (ISBI 2026). Our best-performing model is a fine-tuned DINOBloom-base, on which we train multiple classifier head families (linear, cosine, and multilayer perceptron (MLP)). The cosine head performed best on the mature granulocyte boundary (Band neutrophil (BNE) F1 = 0.470), the linear head on more immature granulocyte classes (Metamyelocyte (MMY) F1 = 0.585), and the MLP head on the most immature granulocyte (Promyelocyte (PMY) F1 = 0.733), revealing class-specific specialization. Based on this specialization, we construct a head-diverse ensemble, where the MLP head acts as the primary predictor, and its predictions within the four predefined confusion pairs are replaced only when two other head families agree. We further show that cases consistently misclassified by all models are substantially enriched for probable labeling errors or inherent morphological ambiguity.

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

Induced pluripotent stem cell (iPSC) culture increasingly relies on segmentation foundation models, yet deployment on laboratory CPUs and edge hardware requires compression schemes that are both efficient and auditable. We present a deployment-oriented evaluation of compressed Cellpose-SAM using a pre-specified retention criterion: the 95% cluster-bootstrap interval of mean change from FP32 must remain above a fixed -0.02 margin for every imaging modality. On a stratified 176-field panel spanning BBBC038 nuclei, BBBC039 U2OS fluorescence, and NIST iPSC images across density regimes, weight-only W8A16 preserves instance F1 across all modalities. A sensitivity-guided mixed W4/W8 scheme, using four INT8 exceptions, achieves a 6.76x reduction in weight storage with no observed catastrophic failures (0/176 fields), matching W8A16 at this sample size. In contrast, ternary weight-only quantization achieves 12.08x compression but fails catastrophically on 169/176 fields. These results demonstrate that compression should be evaluated by modality-stratified downstream retention rather than single-number accuracy, and establish a reproducible protocol for auditing compressed foundation models in regulated stem-cell imaging.

Despite the success of deep learning for text and image data, tree-based ensemble models are still state-of-the-art for machine learning with heterogeneous tabular data. However, there is a significant need for tabular-specific gradient-based methods due to their high flexibility. In this paper, we propose GRANDE, GRAdieNt-Based Decision Tree Ensembles, a novel approach for learning hard, axis-aligned decision tree ensembles using end-to-end gradient descent. GRANDE is based on a dense representation of tree ensembles, which affords to use backpropagation with a straight-through operator to jointly optimize all model parameters. Our method combines axis-aligned splits, which is a useful inductive bias for tabular data, with the flexibility of gradient-based optimization. Furthermore, we introduce an advanced instance-wise weighting that facilitates learning representations for both, simple and complex relations, within a single model. We conducted an extensive evaluation on a predefined benchmark with 19 classification datasets and demonstrate that our method outperforms existing gradient-boosting and deep learning frameworks on most datasets. The method is available under: https://github.com/s-marton/GRANDE

Turning the weights to zero when training a neural network helps in reducing the computational complexity at inference. To progressively increase the sparsity ratio in the network without causing sharp weight discontinuities during training, our work combines soft-thresholding and straight-through gradient estimation to update the raw, i.e. non-thresholded, version of zeroed weights. Our method, named ST-3 for straight-through/soft-thresholding/sparse-training, obtains SoA results, both in terms of accuracy/sparsity and accuracy/FLOPS trade-offs, when progressively increasing the sparsity ratio in a single training cycle. In particular, despite its simplicity, ST-3 favorably compares to the most recent methods, adopting differentiable formulations or bio-inspired neuroregeneration principles. This suggests that the key ingredients for effective sparsification primarily lie in the ability to give the weights the freedom to evolve smoothly across the zero state while progressively increasing the sparsity ratio. Source code and weights available at https://github.com/vanderschuea/stthree

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.

While large-scale training data is fundamental for developing capable large language models (LLMs), strategically selecting high-quality data has emerged as a critical approach to enhance training efficiency and reduce computational costs. Current data selection methodologies predominantly rely on static, training-agnostic criteria, failing to account for the dynamic model training and data interactions. In this paper, we propose a new Data Weighting Model (DWM) to adjust the weight of selected data within each batch to achieve a dynamic data utilization during LLM training. Specially, to better capture the dynamic data preference of the trained model, a bi-level optimization framework is implemented to update the weighting model. Our experiments demonstrate that DWM enhances the performance of models trained with randomly-selected data, and the learned weighting model can be transferred to enhance other data selection methods and models of different sizes. Moreover, we further analyze how a model's data preferences evolve throughout training, providing new insights into the data preference of the model during training.

Scoring systems are linear classification models that only require users to add, subtract and multiply a few small numbers in order to make a prediction. These models are in widespread use by the medical community, but are difficult to learn from data because they need to be accurate and sparse, have coprime integer coefficients, and satisfy multiple operational constraints. We present a new method for creating data-driven scoring systems called a Supersparse Linear Integer Model (SLIM). SLIM scoring systems are built by solving an integer program that directly encodes measures of accuracy (the 0-1 loss) and sparsity (the ell_0-seminorm) while restricting coefficients to coprime integers. SLIM can seamlessly incorporate a wide range of operational constraints related to accuracy and sparsity, and can produce highly tailored models without parameter tuning. We provide bounds on the testing and training accuracy of SLIM scoring systems, and present a new data reduction technique that can improve scalability by eliminating a portion of the training data beforehand. Our paper includes results from a collaboration with the Massachusetts General Hospital Sleep Laboratory, where SLIM was used to create a highly tailored scoring system for sleep apnea screening

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.

Diffusion and flow-matching schedules control the signal and noise coefficients that mix data and noise along affine probability paths. Minimizing a kinetic action defined on coefficient paths, motivated by optimal transport, helps explain strong baselines but remains model-agnostic and ignores prediction error. Here we introduce a model-aware schedule construction based on fiberwise optimal transport. At a fixed time and state on the probability path, compatible signal/noise decompositions form an affine fiber. We define a fiberwise prediction risk by averaging optimal-transport costs between the true and predictor-induced decompositions within these fibers. On a fixed coefficient curve, combining this risk with coefficient-path kinetic action yields a closed-form optimal time allocation. This construction extends to general linear prediction targets, and the risk profile can be estimated from an early baseline checkpoint. We evaluate DDPMs and flow matching across prediction targets, training configurations, risk-estimation checkpoints, datasets, and architectures. Our model-aware schedules consistently outperform strong baselines, including a 38.6% relative FID reduction for flow matching on CIFAR-10 at 16 function evaluations. Each model-agnostic kinetic baseline determines its own kinetic reference coordinate. In these coordinates, fiberwise-risk profiles from independently trained models in different settings align closely after normalization to unit area. The resulting schedule deformations used in training also align, suggesting empirical universality across the evaluated models and settings. Pretrained-checkpoint diagnostics extend this normalized-risk agreement to larger conditional latent diffusion and 2-RF models. A frozen analytic allocation template retains most of the model-aware improvement without further risk estimation or model-specific fitting.

Learning the underlying dynamics of single cells from snapshot data has gained increasing attention in scientific and machine learning research. The destructive measurement technique and cell proliferation/death result in unpaired and unbalanced data between snapshots, making the learning of the underlying dynamics challenging. In this paper, we propose joint Velocity-Growth Flow Matching (VGFM), a novel paradigm that jointly learns state transition and mass growth of single-cell populations via flow matching. VGFM builds an ideal single-cell dynamics containing velocity of state and growth of mass, driven by a presented two-period dynamic understanding of the static semi-relaxed optimal transport, a mathematical tool that seeks the coupling between unpaired and unbalanced data. To enable practical usage, we approximate the ideal dynamics using neural networks, forming our joint velocity and growth matching framework. A distribution fitting loss is also employed in VGFM to further improve the fitting performance for snapshot data. Extensive experimental results on both synthetic and real datasets demonstrate that VGFM can capture the underlying biological dynamics accounting for mass and state variations over time, outperforming existing approaches for single-cell dynamics modeling.

This paper introduces a new biologically-inspired training method named Continual Learning through Adjustment Suppression and Sparsity Promotion (CLASSP). CLASSP is based on two main principles observed in neuroscience, particularly in the context of synaptic transmission and Long-Term Potentiation (LTP). The first principle is a decay rate over the weight adjustment, which is implemented as a generalization of the AdaGrad optimization algorithm. This means that weights that have received many updates should have lower learning rates as they likely encode important information about previously seen data. However, this principle results in a diffuse distribution of updates throughout the model, as it promotes updates for weights that haven't been previously updated, while a sparse update distribution is preferred to leave weights unassigned for future tasks. Therefore, the second principle introduces a threshold on the loss gradient. This promotes sparse learning by updating a weight only if the loss gradient with respect to that weight is above a certain threshold, i.e. only updating weights with a significant impact on the current loss. Both principles reflect phenomena observed in LTP, where a threshold effect and a gradual saturation of potentiation have been observed. CLASSP is implemented in a Python/PyTorch class, making it applicable to any model. When compared with Elastic Weight Consolidation (EWC) using Computer Vision and sentiment analysis datasets, CLASSP demonstrates superior performance in terms of accuracy and memory footprint.

Learning synaptic weights of spiking neural network (SNN) models that can reproduce target spike trains from provided neural firing data is a central problem in computational neuroscience and spike-based computing. The discovery of the optimal weight values can be posed as a supervised learning task wherein the weights of the model network are chosen to maximize the similarity between the target spike trains and the model outputs. It is still largely unknown whether optimizing spike train similarity of highly recurrent SNNs produces weight matrices similar to those of the ground truth model. To this end, we propose flexible heuristic supervised learning rules, termed Pre-Synaptic Pool Modification (PSPM), that rely on stochastic weight updates in order to produce spikes within a short window of the desired times and eliminate spikes outside of this window. PSPM improves spike train similarity for all-to-all SNNs and makes no assumption about the post-synaptic potential of the neurons or the structure of the network since no gradients are required. We test whether optimizing for spike train similarity entails the discovery of accurate weights and explore the relative contributions of local and homeostatic weight updates. Although PSPM improves similarity between spike trains, the learned weights often differ from the weights of the ground truth model, implying that connectome inference from spike data may require additional constraints on connectivity statistics. We also find that spike train similarity is sensitive to local updates, but other measures of network activity such as avalanche distributions, can be learned through synaptic homeostasis.

Domain reweighting is an emerging research area aimed at adjusting the relative weights of different data sources to improve the effectiveness and efficiency of LLM pre-training. We show that data mixtures that perform well at smaller scales may not retain their advantage at larger scales, challenging the existing practice of determining competitive mixtures in small-scale experiments and directly applying them at much larger scales. To address this, we propose AutoScale, a two-stage, scale-aware data composition framework. First, AutoScale fits a parametric model that predicts the model's loss under different data compositions, then uses it to find an approximate best allocation at smaller, more manageable budgets. Next, leveraging a novel theoretical analysis of how optimal compositions evolve with scale, AutoScale extrapolates that composition to larger budgets without further retraining. Empirically, AutoScale accelerates convergence and improves downstream performance. For instance, when pre-training GPT-2 Large, it achieves a 28% faster perplexity reduction than baselines and up to a 38% speed-up over unweighted training, while yielding best-average results on various downstream tasks. Overall, our findings illustrate how domain importance shifts with training scale, underscoring the need for scale-dependent data curation in LLM training. Our code is open-sourced.

Longitudinal single cell atlases now capture matched pre treatment and post treatment states from responders and non responders, presenting an opportunity to mechanistically explain why two patients on the same drug diverge. We introduce scDEFT (single cell Drug EFfect Transducer), which treats a drug as a conditioning operator on cell representations, enabling prediction and explanation. In scDEFT, feature wise linear modulation produces drug conditioned cell latents, learned under abundant per cell supervision and then frozen. Two independent heads aggregate those latents over shared transcriptional neighborhoods to predict drug induced state change and responder status. A backward stage ranks the latent dimensions by how strongly they separate responders from non responders and maps them to genes under a cell composition control. On a harmonized inflammatory bowel disease atlas of 1.16 million cells, three cohorts and two drug classes, scDEFT predicts state change at 45% of the baseline to reproducibility ceiling headroom and stratifies responders before treatment at AUROC 0.70, where standard predictors remain at chance. These predictions and the drivers behind them support target and co target nomination, patient stratification, and counterfactual prediction of unseen drug cohort effects.

Metric space magnitude, an active field of research in algebraic topology, is a scalar quantity that summarizes the effective number of distinct points that live in a general metric space. The {\em weighting vector} is a closely-related concept that captures, in a nontrivial way, much of the underlying geometry of the original metric space. Recent work has demonstrated that when the metric space is Euclidean, the weighting vector serves as an effective tool for boundary detection. We recast this result and show the weighting vector may be viewed as a solution to a kernelized SVM. As one consequence, we apply this new insight to the task of outlier detection, and we demonstrate performance that is competitive or exceeds performance of state-of-the-art techniques on benchmark data sets. Under mild assumptions, we show the weighting vector, which has computational cost of matrix inversion, can be efficiently approximated in linear time. We show how nearest neighbor methods can approximate solutions to the minimization problems defined by SVMs.

Weight initialization plays an important role in neural network training. Widely used initialization methods are proposed and evaluated for networks that are trained from scratch. However, the growing number of pretrained models now offers new opportunities for tackling this classical problem of weight initialization. In this work, we introduce weight selection, a method for initializing smaller models by selecting a subset of weights from a pretrained larger model. This enables the transfer of knowledge from pretrained weights to smaller models. Our experiments demonstrate that weight selection can significantly enhance the performance of small models and reduce their training time. Notably, it can also be used together with knowledge distillation. Weight selection offers a new approach to leverage the power of pretrained models in resource-constrained settings, and we hope it can be a useful tool for training small models in the large-model era. Code is available at https://github.com/OscarXZQ/weight-selection.

Whole-slide images (WSIs) are gigapixel-scale digital scans of histopathology tissue and serve as the primary basis for cancer diagnosis. Existing histopathology generative models operate at the patch scale, producing fixed-size tiles of at most 1024times1024 pixels which encompass only a small fraction of the WSI. In contrast, text reports for clinical diagnoses and slide-level diagnostic labels -- the supervision that exists at scale -- operate at the whole-slide level. We present BigCell, the first approach to generate coherent whole-slide histopathology images at native gigapixel resolution. BigCell trains a flow-matching transformer at 2048times2048 pixels on over 120,000 publicly available WSIs spanning multiple organ types. Conditioning on embeddings from pathology foundation models and using an inference-time sliding-window pipeline, BigCell generates coherent images of up to 32,768times32,768 pixels, outperforming prior tile generators on both tile-level and slide-level fidelity metrics. To make gigapixel synthesis practical, we introduce an adaptive scheduling strategy that prioritizes important slide regions, speeding up image generation by over 3\ttimes with minimal quality degradation. Furthermore, we propose the first text-to-image synthesis at 8k resolution by training a separate model that produces dense conditioning grids directly from pathology text reports. We demonstrate that augmenting with synthetic samples improves slide-level few-shot classification performance by up to 18 % over baselines trained on real data.

Single-cell and spatial foundation models promise transferable biological representations, yet their generality remains largely untested across modalities, biological domains and analytical tasks. We benchmarked six representative models, Nicheformer, CellPLM, scGPT-spatial, GenePT, scELMo and Novae, using a harmonised framework spanning scRNA-seq, spatial transcriptomics and Perturb-seq. We evaluated zero-shot and continually pretrained clustering, supervised annotation, marker-gene concordance and perturbation prediction. Model performance was strongly conditional: expression-trained cell-level transformers best resolved many cell-identity tasks, spatial and graph-aware models better preserved tissue architecture, and language-derived gene embeddings were competitive for selected perturbation-response metrics. No model dominated across tasks, and rankings shifted with modality, preprocessing, tokenisation, biological prior, domain shift and metric choice. This benchmark provides practical guidance for model selection and argues that future models should be judged by biological generalisation, interpretability and perturbation-grounded validity, not by scale or leaderboard performance alone.

Using the weights of trained Neural Network (NN) models as data modality has recently gained traction as a research field - dubbed Weight Space Learning (WSL). Multiple recent works propose WSL methods to analyze models, evaluate methods, or synthesize weights. Weight space learning methods require populations of trained models as datasets for development and evaluation. However, existing collections of models - called `model zoos' - are unstructured or follow a rudimentary definition of diversity. In parallel, work rooted in statistical physics has identified phases and phase transitions in NN models. Models are homogeneous within the same phase but qualitatively differ from one phase to another. We combine the idea of `model zoos' with phase information to create a controlled notion of diversity in populations. We introduce 12 large-scale zoos that systematically cover known phases and vary over model architecture, size, and datasets. These datasets cover different modalities, such as computer vision, natural language processing, and scientific ML. For every model, we compute loss landscape metrics and validate full coverage of the phases. With this dataset, we provide the community with a resource with a wide range of potential applications for WSL and beyond. Evidence suggests the loss landscape phase plays a role in applications such as model training, analysis, or sparsification. We demonstrate this in an exploratory study of the downstream methods like transfer learning or model weights averaging.

Low-Rank Adaptation (LoRA) has achieved remarkable training results by freezing the original weights and training only low-rank matrices, establishing itself as the predominant fine-tuning method for LLMs. In pursuit of performance closer to full-parameter training, a series of LoRA variants have emerged, such as LoRA+, PISSA, Olora, and LoRA-GA. However, these improvements complicate the initial setup of model training and increase initialization time. More importantly, they overlook the internal interactions of the original weight information. To address these issues, we introduce a novel theory, ``Weight Guide'' aimed at continuously guiding trainable matrices through the original weights during training to enhance the utilization of weight information. Based on this theory, we designed a new PEFT technique called Bone (Block Affine), which not only enhances the utilization of original weight information but also emphasizes the internal connections between weights, leading to faster convergence and better data fitting. Experimental comparisons across two different LLM architectures (LLaMA2, RWKV6) and various parameter scales demonstrate that the Bone structure can achieve rapid convergence and superior data fitting without the need for complex initialization. For example, when fine-tuning LLaMA2-7B on the MetaMathQA dataset and validating on GSM8k and math benchmarks, Bone achieved fine-tuning scores of 49.36 and 8.8, respectively, outperforming PISSA by 5.84\% and 1.96\%.

Multi-class tissue-type classification of colorectal cancer (CRC) histopathologic images is a significant step in the development of downstream machine learning models for diagnosis and treatment planning. However, existing public CRC datasets often lack morphologic diversity, suffer from class imbalance, and contain low-quality image tiles, limiting model performance and generalizability. To address these issues, we introduce STARC-9 (STAnford coloRectal Cancer), a large-scale dataset for multi-class tissue classification. STARC-9 contains 630,000 hematoxylin and eosin-stained image tiles uniformly sampled across nine clinically relevant tissue classes (70,000 tiles per class) from 200 CRC patients at the Stanford University School of Medicine. The dataset was built using a novel framework, DeepCluster++, designed to ensure intra-class diversity and reduce manual curation. First, an encoder from a histopathology-specific autoencoder extracts feature vectors from tiles within each whole-slide image. Then, K-means clustering groups morphologically similar tiles, followed by equal-frequency binning to sample diverse morphologic patterns within each class. The selected tiles are subsequently verified by expert gastrointestinal pathologists to ensure accuracy. This semi-automated process significantly reduces manual effort while producing high-quality, diverse tiles. To evaluate STARC-9, we benchmarked convolutional neural networks, transformers, and pathology-specific foundation models on multi-class CRC tissue classification and segmentation tasks, showing superior generalizability compared to models trained on existing datasets. Although we demonstrate the utility of DeepCluster++ on CRC as a pilot use-case, it is a flexible framework that can be used for constructing high-quality datasets from large WSI repositories across a wide range of cancer and non-cancer applications.

An obstacle to artificial general intelligence is set by continual learning of multiple tasks of different nature. Recently, various heuristic tricks, both from machine learning and from neuroscience angles, were proposed, but they lack a unified theory ground. Here, we focus on continual learning in single-layered and multi-layered neural networks of binary weights. A variational Bayesian learning setting is thus proposed, where the neural networks are trained in a field-space, rather than gradient-ill-defined discrete-weight space, and furthermore, weight uncertainty is naturally incorporated, and modulates synaptic resources among tasks. From a physics perspective, we translate the variational continual learning into Franz-Parisi thermodynamic potential framework, where previous task knowledge acts as a prior and a reference as well. We thus interpret the continual learning of the binary perceptron in a teacher-student setting as a Franz-Parisi potential computation. The learning performance can then be analytically studied with mean-field order parameters, whose predictions coincide with numerical experiments using stochastic gradient descent methods. Based on the variational principle and Gaussian field approximation of internal preactivations in hidden layers, we also derive the learning algorithm considering weight uncertainty, which solves the continual learning with binary weights using multi-layered neural networks, and performs better than the currently available metaplasticity algorithm. Our proposed principled frameworks also connect to elastic weight consolidation, weight-uncertainty modulated learning, and neuroscience inspired metaplasticity, providing a theory-grounded method for the real-world multi-task learning with deep networks.

Large language models have shown outstanding performance on text-first tasks such as coding, math, and writing. Recent efforts are shifting models' training to include scientific problems that often live in highly specialized domains beyond text, such as protein structure and biological images. However, in these scenarios, their general-purpose accuracy compared with specialized algorithms remains in question. One such domain is cell tracking, which requires spatiotemporal awareness of cell dynamics. To evaluate this, we created a new benchmark, CellTrack-Bench, which assesses Vision-Language Models' (VLMs) cell-tracking-related performance against specialized trackers. The full benchmark draws from 15 standard cell-tracking datasets across four imaging modalities and comprises 1,537 problems corresponding to 9,041 cell-linking decisions. We selected a hard subset requiring greater reasoning effort by identifying failures shared across distinct algorithmic trackers. With this proposed dataset, we: (i) evaluated different environment harnesses for VLMs; (ii) benchmarked 9 frontier closed-source models and 13 open-weight models; and (iii) provided a detailed analysis of their failure modes. Code, the stored model outputs, and a pipeline that regenerates the benchmark from the source datasets are available at https://github.com/royerlab/celltrack-bench.

Comprehensively characterizing cellular diversity is critical for understanding tissue development, identifying disease-associated populations and investigating gene programmes linked to specialized functions. Advances in single-cell profiling reveal additional cell-specific transcripts and molecular associations, yet many foundation models represent only a restricted portion of this increasingly rich molecular information. Here we present CellNet, which enables panoramic modelling of single-cell transcriptomes by integrating DNA-derived gene identities and measured RNA expression in a shared image representation. Pretrained on 231 million cell profiles spanning 40 species, CellNet improves rare-population and condition-associated state recognition in evaluated cohorts while retaining competitive general cell representations. It predicts withheld coding-gene expression and selected non-coding targets in total-RNA data, and recovers lineage-specific expression patterns in spatial measurements. Prediction also extends across species, including to targets without expression-pretraining exposure. Its gene representations retrieve known non-coding modules and developmental or neural programmes, including from sparsely detected RNA queries. Together, these results establish CellNet as a scalable framework for interpreting cellular diversity through increasingly comprehensive transcriptomic measurements.

Predicting how cells respond to genetic perturbations is fundamental to understanding gene function, disease mechanisms, and therapeutic development. While recent deep learning approaches have shown promise in modeling single-cell perturbation responses, they struggle to generalize across cell types and perturbation contexts due to limited contextual information during generation. We introduce PT-RAG (Perturbation-aware Two-stage Retrieval-Augmented Generation), a novel framework that extends Retrieval-Augmented Generation beyond traditional language-model applications to cellular biology. Unlike standard RAG systems designed for text retrieval with pre-trained LLMs, perturbation retrieval lacks established similarity metrics and requires learning what constitutes relevant context, making differentiable retrieval essential. PT-RAG addresses this through a two-stage pipeline: first, retrieving candidate perturbations K using GenePT embeddings, then adaptively refining the selection through Gumbel-Softmax discrete sampling conditioned on both the cell state and the input perturbation. This cell-type-aware differentiable retrieval enables end-to-end optimization of the retrieval objective jointly with generation. On the Replogle-Nadig single-gene perturbation dataset, we demonstrate that PT-RAG outperforms both STATE and vanilla RAG under identical experimental conditions, with the strongest gains in distributional similarity metrics (W_1, W_2). Notably, vanilla RAG's dramatic failure is itself a key finding: it demonstrates that differentiable, cell-type-aware retrieval is essential in this domain, and that naive retrieval can actively harm performance. Our results establish retrieval-augmented generation as a promising paradigm for modelling cellular responses to gene perturbation. The code to reproduce our experiments is available at https://github.com/difra100/PT-RAG_ICLR.

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

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

Cell Painting is a high-content morphological profiling assay widely used for phenotype-based biological inference, with mechanism of action (MOA) prediction as a central application. Existing approaches largely formulate Cell Painting-based inference as representation matching, assigning predictions from nearby reference perturbations in morphological feature space. However, retrieved neighbors are often noisy and partially misleading evidence due to batch effects, non-specific cytotoxicity, phenotypic convergence, and source-dependent variability. We reformulate Cell Painting-based MOA prediction as a calibrated evidence reasoning problem, where retrieved neighbors are treated as uncertain observations that must be evaluated, compared, and sometimes rejected before supporting a mechanistic conclusion. We propose PhenoAIR, a reliability-aware multi-agent framework that maintains a candidate-centric evidence memory and performs controller-guided refinement over phenotype- and mechanism-side evidence. PhenoAIR uses offline reference-set calibration to weight evidence by source reliability, phenotype stability, and mechanism-level confusion. We evaluate PhenoAIR on a benchmark constructed from JUMP Cell Painting profiles and annotations, covering controlled, realistic, and discovery-oriented open-world MOA prediction settings. PhenoAIR outperforms representation-matching and LLM-based baselines across all settings.

Standard neural networks struggle to generalize under distribution shifts in computer vision. Fortunately, combining multiple networks can consistently improve out-of-distribution generalization. In particular, weight averaging (WA) strategies were shown to perform best on the competitive DomainBed benchmark; they directly average the weights of multiple networks despite their nonlinearities. In this paper, we propose Diverse Weight Averaging (DiWA), a new WA strategy whose main motivation is to increase the functional diversity across averaged models. To this end, DiWA averages weights obtained from several independent training runs: indeed, models obtained from different runs are more diverse than those collected along a single run thanks to differences in hyperparameters and training procedures. We motivate the need for diversity by a new bias-variance-covariance-locality decomposition of the expected error, exploiting similarities between WA and standard functional ensembling. Moreover, this decomposition highlights that WA succeeds when the variance term dominates, which we show occurs when the marginal distribution changes at test time. Experimentally, DiWA consistently improves the state of the art on DomainBed without inference overhead.

Optimal transport (OT) compares probability distributions by computing a meaningful alignment between their samples. CO-optimal transport (COOT) takes this comparison further by inferring an alignment between features as well. While this approach leads to better alignments and generalizes both OT and Gromov-Wasserstein distances, we provide a theoretical result showing that it is sensitive to outliers that are omnipresent in real-world data. This prompts us to propose unbalanced COOT for which we provably show its robustness to noise in the compared datasets. To the best of our knowledge, this is the first such result for OT methods in incomparable spaces. With this result in hand, we provide empirical evidence of this robustness for the challenging tasks of heterogeneous domain adaptation with and without varying proportions of classes and simultaneous alignment of samples and features across single-cell measurements.

Understanding spatial location and relationships is a fundamental capability for modern artificial intelligence systems. Insights from human spatial cognition provide valuable guidance in this domain. Neuroscientific discoveries have highlighted the role of grid cells as a fundamental neural component for spatial representation, including distance computation, path integration, and scale discernment. In this paper, we introduce a novel positional encoding scheme inspired by Fourier analysis and the latest findings in computational neuroscience regarding grid cells. Assuming that grid cells encode spatial position through a summation of Fourier basis functions, we demonstrate the translational invariance of the grid representation during inner product calculations. Additionally, we derive an optimal grid scale ratio for multi-dimensional Euclidean spaces based on principles of biological efficiency. Utilizing these computational principles, we have developed a Grid-cell inspired Positional Encoding technique, termed GridPE, for encoding locations within high-dimensional spaces. We integrated GridPE into the Pyramid Vision Transformer architecture. Our theoretical analysis shows that GridPE provides a unifying framework for positional encoding in arbitrary high-dimensional spaces. Experimental results demonstrate that GridPE significantly enhances the performance of transformers, underscoring the importance of incorporating neuroscientific insights into the design of artificial intelligence systems.

Multimodal alignment of histopathology encoders with transcriptomic and genomic data has been shown to significantly improve performance in downstream diagnostic tasks. Hematological cytology is unique in that visual single-cell evaluation is often paired with cytogenetics and molecular genetics for blood cancer diagnosis. In this study, we present a framework to align single white blood cell images with chromosomal aberrations (karyotype) and somatic mutations from targeted gene panels. Our training strategy follows a two-stage approach: (i) self-supervised, vision-only pretraining of a transformer aggregator using an iBOT head on a cohort of over 1500 patients, and (ii) genetic alignment via supervised contrastive loss on acute myeloid leukemia patients. Our genetically aligned patient encoder improves hematological diagnostic tasks, outperforming slide-level histopathology foundation models. Additionally, the model provides off-the-shelf retrieval capabilities for diseases and genetic alterations. Incorporating genetic data into patient encoders increases the quality of patient representations, providing a framework that aligns with clinical diagnostic workflows and paves the way for future multimodal hematology-specific AI. The code and model weights are available at https://github.com/marrlab/GenBloom.

Automated model selection is often proposed to users to choose which machine learning model (or method) to apply to a given regression task. In this paper, we show that combining different regression models can yield better results than selecting a single ('best') regression model, and outline an efficient method that obtains optimally weighted convex linear combination from a heterogeneous set of regression models. More specifically, in this paper, a heuristic weight optimization, used in a preceding conference paper, is replaced by an exact optimization algorithm using convex quadratic programming. We prove convexity of the quadratic programming formulation for the straightforward formulation and for a formulation with weighted data points. The novel weight optimization is not only (more) exact but also more efficient. The methods we develop in this paper are implemented and made available via github-open source. They can be executed on commonly available hardware and offer a transparent and easy to interpret interface. The results indicate that the approach outperforms model selection methods on a range of data sets, including data sets with mixed variable type from drug discovery applications.

For learning with noisy labels, the transition matrix, which explicitly models the relation between noisy label distribution and clean label distribution, has been utilized to achieve the statistical consistency of either the classifier or the risk. Previous researches have focused more on how to estimate this transition matrix well, rather than how to utilize it. We propose good utilization of the transition matrix is crucial and suggest a new utilization method based on resampling, coined RENT. Specifically, we first demonstrate current utilizations can have potential limitations for implementation. As an extension to Reweighting, we suggest the Dirichlet distribution-based per-sample Weight Sampling (DWS) framework, and compare reweighting and resampling under DWS framework. With the analyses from DWS, we propose RENT, a REsampling method with Noise Transition matrix. Empirically, RENT consistently outperforms existing transition matrix utilization methods, which includes reweighting, on various benchmark datasets. Our code is available at https://github.com/BaeHeeSun/RENT.

We propose Beam Tree Recursive Cell (BT-Cell) - a backpropagation-friendly framework to extend Recursive Neural Networks (RvNNs) with beam search for latent structure induction. We further extend this framework by proposing a relaxation of the hard top-k operators in beam search for better propagation of gradient signals. We evaluate our proposed models in different out-of-distribution splits in both synthetic and realistic data. Our experiments show that BTCell achieves near-perfect performance on several challenging structure-sensitive synthetic tasks like ListOps and logical inference while maintaining comparable performance in realistic data against other RvNN-based models. Additionally, we identify a previously unknown failure case for neural models in generalization to unseen number of arguments in ListOps. The code is available at: https://github.com/JRC1995/BeamTreeRecursiveCells.

Designing machine learning architectures for processing neural networks in their raw weight matrix form is a newly introduced research direction. Unfortunately, the unique symmetry structure of deep weight spaces makes this design very challenging. If successful, such architectures would be capable of performing a wide range of intriguing tasks, from adapting a pre-trained network to a new domain to editing objects represented as functions (INRs or NeRFs). As a first step towards this goal, we present here a novel network architecture for learning in deep weight spaces. It takes as input a concatenation of weights and biases of a pre-trained MLP and processes it using a composition of layers that are equivariant to the natural permutation symmetry of the MLP's weights: Changing the order of neurons in intermediate layers of the MLP does not affect the function it represents. We provide a full characterization of all affine equivariant and invariant layers for these symmetries and show how these layers can be implemented using three basic operations: pooling, broadcasting, and fully connected layers applied to the input in an appropriate manner. We demonstrate the effectiveness of our architecture and its advantages over natural baselines in a variety of learning tasks.

We present WBCBench 2026, an ISBI challenge and benchmark for automated WBC classification designed to stress-test algorithms under three key difficulties: (i) severe class imbalance across 13 morphologically fine-grained WBC classes, (ii) strict patient-level separation between training, validation and test sets, and (iii) synthetic scanner- and setting-induced domain shift via controlled noise, blur and illumination perturbations. All images are single-site microscopic blood smear acquisitions with standardised staining and expert hematopathologist annotations. This paper reviews the challenge and summarises the proposed solutions and final outcomes. The benchmark is organised into two phases. Phase 1 provides a pristine training set. Phase 2 introduces degraded images with split-specific severity distributions for train, validation and test, emulating a realistic shift between development and deployment conditions. We specify a standardised submission schema, open-source evaluator, and macro-averaged F1 score as the primary ranking metric.

Forward-Forward (FF) training allows each layer to learn from a local goodness criterion. In cumulative-goodness variants, however, later layers can inherit a task that earlier layers have already partially separated. We formalize this phenomenon as layer free-riding: under the softplus FF criterion, the class-discrimination gradient reaching block d decays exponentially with the positive margin accumulated by preceding blocks. We then study three local remedies -- per-block, hardness-gated, and depth-scaled -- that recover current-layer separation measures without relying on backpropagated gradients. On CIFAR-10 and CIFAR-100, these remedies dramatically improve layer-separation statistics, with 4times--45times gains in deeper layers, while changing accuracy by less than one percentage point for non-degenerate training procedures. Tiny ImageNet provides a tougher cross-dataset check for our selected block-wise configuration and reveals the same qualitative gap between layer-health diagnostics and final accuracy. Calibration experiments further show that architecture and augmentation choices have a larger effect on final accuracy than the training-rule modifications studied here. Cumulative free-riding is therefore a real and repairable optimization pathology. Nonetheless, for the FF training rules, architectures, and datasets we study, it is not the dominant factor limiting achievable accuracy.

Deep learning-based electrocardiogram (ECG) classification has shown impressive performance but clinical adoption has been slowed by the lack of transparent and faithful explanations. Post hoc methods such as saliency maps may fail to reflect a model's true decision process. Prototype-based reasoning offers a more transparent alternative by grounding decisions in similarity to learned representations of real ECG segments, enabling faithful, case-based explanations. We introduce ProtoECGNet, a prototype-based deep learning model for interpretable, multi-label ECG classification. ProtoECGNet employs a structured, multi-branch architecture that reflects clinical interpretation workflows: it integrates a 1D CNN with global prototypes for rhythm classification, a 2D CNN with time-localized prototypes for morphology-based reasoning, and a 2D CNN with global prototypes for diffuse abnormalities. Each branch is trained with a prototype loss designed for multi-label learning, combining clustering, separation, diversity, and a novel contrastive loss that encourages appropriate separation between prototypes of unrelated classes while allowing clustering for frequently co-occurring diagnoses. We evaluate ProtoECGNet on all 71 diagnostic labels from the PTB-XL dataset, demonstrating competitive performance relative to state-of-the-art black-box models while providing structured, case-based explanations. To assess prototype quality, we conduct a structured clinician review of the final model's projected prototypes, finding that they are rated as representative and clear. ProtoECGNet shows that prototype learning can be effectively scaled to complex, multi-label time-series classification, offering a practical path toward transparent and trustworthy deep learning models for clinical decision support.

Volumetry is one of the principal downstream applications of 3D medical image segmentation, for example, to detect abnormal tissue growth or for surgery planning. Conformal Prediction is a promising framework for uncertainty quantification, providing calibrated predictive intervals associated with automatic volume measurements. However, this methodology is based on the hypothesis that calibration and test samples are exchangeable, an assumption that is in practice often violated in medical image applications. A weighted formulation of Conformal Prediction can be framed to mitigate this issue, but its empirical investigation in the medical domain is still lacking. A potential reason is that it relies on the estimation of the density ratio between the calibration and test distributions, which is likely to be intractable in scenarios involving high-dimensional data. To circumvent this, we propose an efficient approach for density ratio estimation relying on the compressed latent representations generated by the segmentation model. Our experiments demonstrate the efficiency of our approach to reduce the coverage error in the presence of covariate shifts, in both synthetic and real-world settings. Our implementation is available at https://github.com/benolmbrt/wcp_miccai

In this paper, we present a simple yet effective provable method (named ABSGD) for addressing the data imbalance or label noise problem in deep learning. Our method is a simple modification to momentum SGD where we assign an individual importance weight to each sample in the mini-batch. The individual-level weight of sampled data is systematically proportional to the exponential of a scaled loss value of the data, where the scaling factor is interpreted as the regularization parameter in the framework of distributionally robust optimization (DRO). Depending on whether the scaling factor is positive or negative, ABSGD is guaranteed to converge to a stationary point of an information-regularized min-max or min-min DRO problem, respectively. Compared with existing class-level weighting schemes, our method can capture the diversity between individual examples within each class. Compared with existing individual-level weighting methods using meta-learning that require three backward propagations for computing mini-batch stochastic gradients, our method is more efficient with only one backward propagation at each iteration as in standard deep learning methods. ABSGD is flexible enough to combine with other robust losses without any additional cost. Our empirical studies on several benchmark datasets demonstrate the effectiveness of the proposed method.Code is available at:\url{https://github.com/qiqi-helloworld/ABSGD/}

Large language models (LLMs) have shown remarkable capability in numerous tasks and applications. However, fine-tuning LLMs using high-quality datasets under external supervision remains prohibitively expensive. In response, LLM self-improvement approaches have been vibrantly developed recently. The typical paradigm of LLM self-improvement involves training LLM on self-generated data, part of which may be detrimental and should be filtered out due to the unstable data quality. While current works primarily employs filtering strategies based on answer correctness, in this paper, we demonstrate that filtering out correct but with high distribution shift extent (DSE) samples could also benefit the results of self-improvement. Given that the actual sample distribution is usually inaccessible, we propose a new metric called DS weight to approximate DSE, inspired by the Importance Weighting methods. Consequently, we integrate DS weight with self-consistency to comprehensively filter the self-generated samples and fine-tune the language model. Experiments show that with only a tiny valid set (up to 5\% size of the training set) to compute DS weight, our approach can notably promote the reasoning ability of current LLM self-improvement methods. The resulting performance is on par with methods that rely on external supervision from pre-trained reward models.

This paper studies the problem of training a two-layer ReLU network for binary classification using gradient flow with small initialization. We consider a training dataset with well-separated input vectors: Any pair of input data with the same label are positively correlated, and any pair with different labels are negatively correlated. Our analysis shows that, during the early phase of training, neurons in the first layer try to align with either the positive data or the negative data, depending on its corresponding weight on the second layer. A careful analysis of the neurons' directional dynamics allows us to provide an O(log n{mu}) upper bound on the time it takes for all neurons to achieve good alignment with the input data, where n is the number of data points and mu measures how well the data are separated. After the early alignment phase, the loss converges to zero at a O(1{t}) rate, and the weight matrix on the first layer is approximately low-rank. Numerical experiments on the MNIST dataset illustrate our theoretical findings.

Robust validation metrics remain essential in contemporary deep learning, not only to detect overfitting and poor generalization, but also to monitor training dynamics. In the supervised classification setting, we investigate whether interactions between training data and model weights can yield such a metric that both tracks generalization during training and attributes performance to individual training samples. We introduce Gradient-Weight Alignment (GWA), quantifying the coherence between per-sample gradients and model weights. We show that effective learning corresponds to coherent alignment, while misalignment indicates deteriorating generalization. GWA is efficiently computable during training and reflects both sample-specific contributions and dataset-wide learning dynamics. Extensive experiments show that GWA accurately predicts optimal early stopping, enables principled model comparisons, and identifies influential training samples, providing a validation-set-free approach for model analysis directly from the training data.

The mathematical problem-solving capabilities of large language models have become a focal point of research, with growing interests in leveraging self-generated reasoning paths as a promising way to refine and enhance these models. These paths capture step-by-step logical processes while requiring only the correct answer for supervision. The self-training method has been shown to be effective in reasoning tasks while eliminating the need for external models and manual annotations. However, optimizing the use of self-generated data for model training remains an open challenge. In this work, we propose Entropy-Based Adaptive Weighting for Self-Training (EAST), an adaptive weighting strategy designed to prioritize uncertain data during self-training. Specifically, EAST employs a mapping function with a tunable parameter that controls the sharpness of the weighting, assigning higher weights to data where the model exhibits greater uncertainty. This approach guides the model to focus on more informative and challenging examples, thereby enhancing its reasoning ability. We evaluate our approach on GSM8K and MATH benchmarks. Empirical results show that, while the vanilla method yields virtually no improvement (0%) on MATH, EAST achieves around a 1% gain over backbone model. On GSM8K, EAST attains a further 1-2% performance boost compared to the vanilla method.

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

Automated red blood cell (RBC) classification on blood smear images helps hematologists to analyze RBC lab results in a reduced time and cost. However, overlapping cells can cause incorrect predicted results, and so they have to be separated into multiple single RBCs before classifying. To classify multiple classes with deep learning, imbalance problems are common in medical imaging because normal samples are always higher than rare disease samples. This paper presents a new method to segment and classify RBCs from blood smear images, specifically to tackle cell overlapping and data imbalance problems. Focusing on overlapping cell separation, our segmentation process first estimates ellipses to represent RBCs. The method detects the concave points and then finds the ellipses using directed ellipse fitting. The accuracy from 20 blood smear images was 0.889. Classification requires balanced training datasets. However, some RBC types are rare. The imbalance ratio of this dataset was 34.538 for 12 RBC classes from 20,875 individual RBC samples. The use of machine learning for RBC classification with an imbalanced dataset is hence more challenging than many other applications. We analyzed techniques to deal with this problem. The best accuracy and F1-score were 0.921 and 0.8679, respectively, using EfficientNet-B1 with augmentation. Experimental results showed that the weight balancing technique with augmentation had the potential to deal with imbalance problems by improving the F1-score on minority classes, while data augmentation significantly improved the overall classification performance.

Biological discovery requires using molecular knowledge and new measurements to infer responses beyond the conditions already observed. We introduce CellCanon, the first agentic cellular world model to unify single-cell expression prediction, evidence-grounded explanation, and observation-driven updating. Its predictive core reuses condition-level biological evidence across gene-specific numerical readouts to guide single-cell expression generation. A shared world state links predictions, acquired measurements, and source-linked claims, supporting explanation and revision. On 339 held-out SciPlex3 conditions across three cell lines, CellCanon improves differential-expression AUPRC and Macro-F1 over the best baseline for each metric by 63.3% and 17.3%, respectively, and direction Macro-F1 by 7.2%. Relative to gene-wise reasoning on matched drug-cell cohorts, measured language-model token use falls by 99.77% for Predict and 98.41% for Explain. On the source-grounded benchmark, Explain correctly answers all answerable questions with supporting proofs and identifies all insufficient-evidence cases. In simulated experimental feedback, Update uses one measured source context per drug to exceed the best fine-tuned baselines in differential-expression AUPRC and Macro-F1 without changing model weights. Together, these capabilities support a cumulative account of cellular responses, with predictions and biological judgments that can be revised as evidence accumulates.

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.

The identification of heterogeneous treatment effects (HTE) across subgroups is of significant interest in clinical trial analysis. Several state-of-the-art HTE estimation methods, including causal forests, apply recursive partitioning for non-parametric identification of relevant covariates and interactions. However, the partitioning criterion is typically based on differences in absolute risk. This can dilute statistical power by masking variation in the relative risk, which is often a more appropriate quantity of clinical interest. In this work, we propose and implement a methodology for modifying causal forests to target relative risk, using a novel node-splitting procedure based on exhaustive generalized linear model comparison. We present results from simulated data that suggest relative risk causal forests can capture otherwise undetected sources of heterogeneity. We implement our method on real-world trial data to explore HTEs for liraglutide in patients with type 2 diabetes.

Large foundation models are typically trained on data from multiple domains, with the data mixture--the proportion of each domain used--playing a critical role in model performance. The standard approach to selecting this mixture relies on trial and error, which becomes impractical for large-scale pretraining. We propose a systematic method to determine the optimal data mixture for any target domain using scaling laws. Our approach accurately predicts the loss of a model of size N trained with D tokens and a specific domain weight vector h. We validate the universality of these scaling laws by demonstrating their predictive power in three distinct and large-scale settings: large language model (LLM), native multimodal model (NMM), and large vision models (LVM) pretraining. We further show that these scaling laws can extrapolate to new data mixtures and across scales: their parameters can be accurately estimated using a few small-scale training runs, and used to estimate the performance at larger scales and unseen domain weights. The scaling laws allow to derive the optimal domain weights for any target domain under a given training budget (N,D), providing a principled alternative to costly trial-and-error methods.

Finding neural network weights that generalize well from small datasets is difficult. A promising approach is to learn a weight initialization such that a small number of weight changes results in low generalization error. We show that this form of meta-learning can be improved by letting the learning algorithm decide which weights to change, i.e., by learning where to learn. We find that patterned sparsity emerges from this process, with the pattern of sparsity varying on a problem-by-problem basis. This selective sparsity results in better generalization and less interference in a range of few-shot and continual learning problems. Moreover, we find that sparse learning also emerges in a more expressive model where learning rates are meta-learned. Our results shed light on an ongoing debate on whether meta-learning can discover adaptable features and suggest that learning by sparse gradient descent is a powerful inductive bias for meta-learning systems.

A recent paper proposed Dynamic Tanh (DyT) as a drop-in replacement for Layer Normalization. Although the method is empirically well-motivated and appealing from a practical point of view, it lacks a theoretical foundation. In this work, we derive DyT mathematically and show that a well-defined approximation is needed to do so. By dropping said approximation, an alternative element-wise transformation is obtained, which we call Elementwise Layer Normalization (ELN). We demonstrate that ELN resembles Layer Normalization more accurately than DyT does.

A proper initialization of the weights in a neural network is critical to its convergence. Current insights into weight initialization come primarily from linear activation functions. In this paper, I develop a theory for weight initializations with non-linear activations. First, I derive a general weight initialization strategy for any neural network using activation functions differentiable at 0. Next, I derive the weight initialization strategy for the Rectified Linear Unit (RELU), and provide theoretical insights into why the Xavier initialization is a poor choice with RELU activations. My analysis provides a clear demonstration of the role of non-linearities in determining the proper weight initializations.

We study a self-supervised generation task for single-cell gene expression vectors: given a set of vectors from a cell type, we aim to generate additional gene expression vectors of that cell type. For this task we characterize both the biological fidelity of the generated gene expression vectors and the scaling behavior of the pretraining loss. The model is a causal transformer paired with a learned quantized VAE tokenizer, trained with a cross-entropy loss. To evaluate the model, we condition it on held-out gene expression vectors of a cell type and generate vectors of gene expression, comparing the resulting distribution over gene expression vectors to the ground truth distribution of that cell type. We study the scaling properties of the proposed architecture by varying the number of trained parameters and the amount of training data. To our knowledge, we find the first jointly-fit two-exponent scaling law and compute-optimal frontier for a single-cell foundation model. Finally, we discuss how this pretrained model could be finetuned for perturbation response prediction.

We apply the Weibull distribution -- a two-parameter family from extreme-value theory -- as a diagnostic framework for element-wise weight magnitude distributions in transformers. At initialization, i.i.d. Gaussian weights give |w| ~ HalfNormal, yielding k ~ 1.20 via middle-80% probability-plot fit (the protocol used throughout this work). This anchor makes k a principled, architecture-independent measuring stick for training dynamics; fitting each weight matrix independently at every layer at every checkpoint enables per-component, per-layer, and per-step diagnostics that aggregate statistics cannot resolve. Applying this framework to 12 model entries spanning 7 architectural families (Pythia, OLMo-1/2, LLaMA-3, Mistral, Qwen2.5/3) reveals three findings. First, FFN modules and the attention output projection W_o -- the Transmission Class -- fall in a narrow k band: median terminal k in [1.186, 1.204] across 12 entries (cross-family CV = 0.51%), shared across SwiGLU/GeLU activations, Pre-LN/QK-Norm placements, and 70M-14B sizes. Second, the attention input projections W_q, W_k -- the Selection Class -- depart from the Weibull family, with severity shaped by storage: separately-stored Q/K (OLMo-1, OLMo-2) yields k in [0.76, 0.99] (deep); GQA models yield k in [1.10, 1.16] (mild); Pythia's merged W_qkv occupies a transitional zone tracking training budget T/tau monotonically. Third, lambda grows substantially during training and scales with sqrt(eta/lambda_wd) within the Pythia family (Pearson r = 0.94, three Transmission kinds), directionally consistent with Fan et al. (2025). The two parameters carry independent information: k labels the functional class, lambda labels training progress. We release npm-weibull-py v0.4 (Python library) and DATABASE_v9_1 at https://github.com/tiexinding/NPM-Weibull-public .

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

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.

Label-free single-cell imaging offers a scalable, non-invasive alternative to fluorescence-based cytometry, yet inferring molecular phenotypes directly from bright-field morphology remains challenging. We present a unified Deep Learning (DL) framework that jointly performs White Blood Cell (WBC) classification and continuous protein-expression regression from label-free Differential Phase Contrast (DPC) images. Our model employs a Hybrid architecture that fuses convolutional fine-grained texture features with transformer-based global representations through a learnable cross-branch gating module, enabling robust morpho-molecular inference from DPC images. To support downstream interpretability, we further incorporate a Large Language Model (LLM) that generates concise, biologically grounded summaries of the predicted cell states. Experiments on the Berkeley Single Cell Computational Microscopy (BSCCM) and Blood Cells Image benchmarks demonstrate strong performance, achieving a 91.3% WBC classification accuracy and a 0.72 Pearson correlation for CD16 expression regression on BSCCM. These results underscore the promise of label-free single-cell imaging for cost-effective hematological profiling, enabling simultaneous phenotype identification and quantitative biomarker estimation without fluorescent staining. The source code is available at https://github.com/saqibnaziir/Single-Cell-Phenotyping.

In this article, we introduce a novel normalization technique for neural network weight matrices, which we term weight conditioning. This approach aims to narrow the gap between the smallest and largest singular values of the weight matrices, resulting in better-conditioned matrices. The inspiration for this technique partially derives from numerical linear algebra, where well-conditioned matrices are known to facilitate stronger convergence results for iterative solvers. We provide a theoretical foundation demonstrating that our normalization technique smoothens the loss landscape, thereby enhancing convergence of stochastic gradient descent algorithms. Empirically, we validate our normalization across various neural network architectures, including Convolutional Neural Networks (CNNs), Vision Transformers (ViT), Neural Radiance Fields (NeRF), and 3D shape modeling. Our findings indicate that our normalization method is not only competitive but also outperforms existing weight normalization techniques from the literature.

Automating white blood cell classification for diagnosis of leukaemia is a promising alternative to time-consuming and resource-intensive examination of cells by expert pathologists. However, designing robust algorithms for classification of rare cell types remains challenging due to variations in staining, scanning and inter-patient heterogeneity. We propose a lightweight ensemble approach for classification of cells during Haematopoiesis, with a focus on the biology of Granulopoiesis, Monocytopoiesis and Lymphopoiesis. Through dataset expansion to alleviate some class imbalance, we demonstrate that a simple ensemble of lightweight pretrained SwinV2-Tiny, DinoBloom-Small and ConvNeXT-V2-Tiny models achieves excellent performance on this challenging dataset. We train 3 instantiations of each architecture in a stratified 3-fold cross-validation framework; for an input image, we forward-pass through all 9 models and aggregate through logit averaging. We further reason on the weaknesses of our model in confusing similar-looking myelocytes in granulopoiesis and lymphocytes in lymphopoiesis. Code: https://gitlab.com/siddharthsrivastava/wbc-bench-2026.

Good weight initialization serves as an effective measure to reduce the training cost of a deep neural network (DNN) model. The choice of how to initialize parameters is challenging and may require manual tuning, which can be time-consuming and prone to human error. To overcome such limitations, this work takes a novel step towards building a weight generator to synthesize the neural weights for initialization. We use the image-to-image translation task with generative adversarial networks (GANs) as an example due to the ease of collecting model weights spanning a wide range. Specifically, we first collect a dataset with various image editing concepts and their corresponding trained weights, which are later used for the training of the weight generator. To address the different characteristics among layers and the substantial number of weights to be predicted, we divide the weights into equal-sized blocks and assign each block an index. Subsequently, a diffusion model is trained with such a dataset using both text conditions of the concept and the block indexes. By initializing the image translation model with the denoised weights predicted by our diffusion model, the training requires only 43.3 seconds. Compared to training from scratch (i.e., Pix2pix), we achieve a 15x training time acceleration for a new concept while obtaining even better image generation quality.

In observational studies, balancing covariates in different treatment groups is essential to estimate treatment effects. One of the most commonly used methods for such purposes is weighting. The performance of this class of methods usually depends on strong regularity conditions for the underlying model, which might not hold in practice. In this paper, we investigate weighting methods from a functional estimation perspective and argue that the weights needed for covariate balancing could differ from those needed for treatment effects estimation under low regularity conditions. Motivated by this observation, we introduce a new framework of weighting that directly targets the treatment effects estimation. Unlike existing methods, the resulting estimator for a treatment effect under this new framework is a simple kernel-based U-statistic after applying a data-driven transformation to the observed covariates. We characterize the theoretical properties of the new estimators of treatment effects under a nonparametric setting and show that they are able to work robustly under low regularity conditions. The new framework is also applied to several numerical examples to demonstrate its practical merits.

Generative modeling has shown increasing promise for predicting cellular perturbation effects under chemical compound treatments. Existing approaches either model perturbation as a distribution-to-distribution mapping without explicit concentration handling, or treat concentration as a discrete class label, precluding continuous dose control. We introduce a joint flow matching approach that simultaneously models cell latents and drug concentration via a dual-timestep formulation, enabling dose-conditioned single-cell morphing through the invertibility of flow matching. The joint formulation induces a monotonic dose-response geometry in latent space and additionally supports concentration estimation from cell morphology. As proof of concept, we further demonstrate generalization to an unseen dose held out during training. Empirically, our method achieves competitive or improved per-concentration metrics on two compounds compared with representative baselines, while enabling capabilities structurally unavailable to discrete-class methods.

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

Metric space magnitude, an active subject of research in algebraic topology, originally arose in the context of biology, where it was used to represent the effective number of distinct species in an environment. In a more general setting, the magnitude of a metric space is a real number that aims to quantify the effective number of distinct points in the space. The contribution of each point to a metric space's global magnitude, which is encoded by the {\em weighting vector}, captures much of the underlying geometry of the original metric space. Surprisingly, when the metric space is Euclidean, the weighting vector also serves as an effective tool for boundary detection. This allows the weighting vector to serve as the foundation of novel algorithms for classic machine learning tasks such as classification, outlier detection and active learning. We demonstrate, using experiments and comparisons on classic benchmark datasets, the promise of the proposed magnitude and weighting vector-based approaches.

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.

As machine learning tasks continue to evolve, the trend has been to gather larger datasets and train increasingly larger models. While this has led to advancements in accuracy, it has also escalated computational costs to unsustainable levels. Addressing this, our work aims to strike a delicate balance between computational efficiency and model accuracy, a persisting challenge in the field. We introduce a novel method that employs core subset selection for reweighting, effectively optimizing both computational time and model performance. By focusing on a strategically selected coreset, our approach offers a robust representation, as it efficiently minimizes the influence of outliers. The re-calibrated weights are then mapped back to and propagated across the entire dataset. Our experimental results substantiate the effectiveness of this approach, underscoring its potential as a scalable and precise solution for model training.

Examining blood microscopic images for leukemia is necessary when expensive equipment for flow cytometry is unavailable. Automated systems can ease the burden on medical experts for performing this examination and may be especially helpful to quickly screen a large number of patients. We present a simple, yet effective classification approach using a ResNeXt convolutional neural network with Squeeze-and-Excitation modules. The approach was evaluated in the C-NMC online challenge and achieves a weighted F1-score of 88.91% on the test set. Code is available at https://github.com/jprellberg/isbi2019cancer