Contrastive learning of cell state dynamics in response to perturbations

We introduce DynaCLR, a self-supervised framework for modeling cell dynamics via contrastive learning of representations of time-lapse datasets. Live cell imaging of cells and organelles is widely used to analyze cellular responses to perturbations. Human annotation of dynamic cell states captured by time-lapse perturbation datasets is laborious and prone to bias. DynaCLR integrates single-cell tracking with time-aware contrastive learning to map images of cells at neighboring time points to neighboring embeddings. Mapping the morphological dynamics of cells to a temporally regularized embedding space makes the annotation, classification, clustering, or interpretation of the cell states more quantitative and efficient. We illustrate the features and applications of DynaCLR with the following experiments: analyzing the kinetics of viral infection in human cells, detecting transient changes in cell morphology due to cell division, and mapping the dynamics of organelles due to viral infection. Models trained with DynaCLR consistently achieve $>95\%$ accuracy for infection state classification, enable the detection of transient cell states and reliably embed unseen experiments. DynaCLR provides a flexible framework for comparative analysis of cell state dynamics due to perturbations, such as infection, gene knockouts, and drugs. We provide PyTorch-based implementations of the model training and inference pipeline (https://github.com/mehta-lab/viscy) and a user interface (https://github.com/czbiohub-sf/napari-iohub) for the visualization and annotation of trajectories of cells in the real space and the embedding space.

Efficient Generation of Molecular Clusters with Dual-Scale Equivariant Flow Matching

Amorphous molecular solids offer a promising alternative to inorganic semiconductors, owing to their mechanical flexibility and solution processability. The packing structure of these materials plays a crucial role in determining their electronic and transport properties, which are key to enhancing the efficiency of devices like organic solar cells (OSCs). However, obtaining these optoelectronic properties computationally requires molecular dynamics (MD) simulations to generate a conformational ensemble, a process that can be computationally expensive due to the large system sizes involved. Recent advances have focused on using generative models, particularly flow-based models as Boltzmann generators, to improve the efficiency of MD sampling. In this work, we developed a dual-scale flow matching method that separates training and inference into coarse-grained and all-atom stages and enhances both the accuracy and efficiency of standard flow matching samplers. We demonstrate the effectiveness of this method on a dataset of Y6 molecular clusters obtained through MD simulations, and we benchmark its efficiency and accuracy against single-scale flow matching methods.

Recovering Manifold Structure Using Ollivier-Ricci Curvature

We introduce ORC-ManL, a new algorithm to prune spurious edges from nearest neighbor graphs using a criterion based on Ollivier-Ricci curvature and estimated metric distortion. Our motivation comes from manifold learning: we show that when the data generating the nearest-neighbor graph consists of noisy samples from a low-dimensional manifold, edges that shortcut through the ambient space have more negative Ollivier-Ricci curvature than edges that lie along the data manifold. We demonstrate that our method outperforms alternative pruning methods and that it significantly improves performance on many downstream geometric data analysis tasks that use nearest neighbor graphs as input. Specifically, we evaluate on manifold learning, persistent homology, dimension estimation, and others. We also show that ORC-ManL can be used to improve clustering and manifold learning of single-cell RNA sequencing data. Finally, we provide empirical convergence experiments that support our theoretical findings.

User Subgrouping in Scalable Cell-Free Massive MIMO Multicasting Systems

Cell-free massive multiple-input multiple-output (CF-mMIMO) is a breakthrough technology for beyond-5G systems, designed to significantly boost the energy and spectral efficiencies of future mobile networks while ensuring a consistent quality of service for all users. Additionally, multicasting has gained considerable attention recently because physical-layer multicasting offers an efficient method for simultaneously serving multiple users with identical service demands by sharing radio resources. Typically, multicast services are delivered either via unicast transmissions or a single multicast transmission. This work, however, introduces a novel subgroup-centric multicast CF-mMIMO framework that divides users into several multicast subgroups based on the similarities in their spatial channel characteristics. This approach allows for efficient sharing of the pilot sequences used for channel estimation and the precoding filters used for data transmission. The proposed framework employs two scalable precoding strategies: centralized improved partial MMSE (IP-MMSE) and distributed conjugate beam-forming (CB). Numerical results show that for scenarios where users are uniformly distributed across the service area, unicast transmissions using centralized IP-MMSE precoding are optimal. However, in cases where users are spatially clustered, multicast subgrouping significantly improves the sum spectral efficiency (SE) of the multicast service compared to both unicast and single multicast transmission. Notably, in clustered scenarios, distributed CB precoding outperforms IP-MMSE in terms of per-user SE, making it the best solution for delivering multicast content.

Hierarchical novel class discovery for single-cell transcriptomic profiles

One of the major challenges arising from single-cell transcriptomics experiments is the question of how to annotate the associated single-cell transcriptomic profiles. Because of the large size and the high dimensionality of the data, automated methods for annotation are needed. We focus here on datasets obtained in the context of developmental biology, where the differentiation process leads to a hierarchical structure. We consider a frequent setting where both labeled and unlabeled data are available at training time, but the sets of the labels of labeled data on one side and of the unlabeled data on the other side, are disjoint. It is an instance of the Novel Class Discovery problem. The goal is to achieve two objectives, clustering the data and mapping the clusters with labels. We propose extensions of k-Means and GMM clustering methods for solving the problem and report comparative results on artificial and experimental transcriptomic datasets. Our approaches take advantage of the hierarchical nature of the data.

Single-cell Curriculum Learning-based Deep Graph Embedding Clustering

The swift advancement of single-cell RNA sequencing (scRNA-seq) technologies enables the investigation of cellular-level tissue heterogeneity. Cell annotation significantly contributes to the extensive downstream analysis of scRNA-seq data. However, The analysis of scRNA-seq for biological inference presents challenges owing to its intricate and indeterminate data distribution, characterized by a substantial volume and a high frequency of dropout events. Furthermore, the quality of training samples varies greatly, and the performance of the popular scRNA-seq data clustering solution GNN could be harmed by two types of low-quality training nodes: 1) nodes on the boundary; 2) nodes that contribute little additional information to the graph. To address these problems, we propose a single-cell curriculum learning-based deep graph embedding clustering (scCLG). We first propose a Chebyshev graph convolutional autoencoder with multi-decoder (ChebAE) that combines three optimization objectives corresponding to three decoders, including topology reconstruction loss of cell graphs, zero-inflated negative binomial (ZINB) loss, and clustering loss, to learn cell-cell topology representation. Meanwhile, we employ a selective training strategy to train GNN based on the features and entropy of nodes and prune the difficult nodes based on the difficulty scores to keep the high-quality graph. Empirical results on a variety of gene expression datasets show that our model outperforms state-of-the-art methods.

scASDC: Attention Enhanced Structural Deep Clustering for Single-cell RNA-seq Data

Single-cell RNA sequencing (scRNA-seq) data analysis is pivotal for understanding cellular heterogeneity. However, the high sparsity and complex noise patterns inherent in scRNA-seq data present significant challenges for traditional clustering methods. To address these issues, we propose a deep clustering method, Attention-Enhanced Structural Deep Embedding Graph Clustering (scASDC), which integrates multiple advanced modules to improve clustering accuracy and robustness.Our approach employs a multi-layer graph convolutional network (GCN) to capture high-order structural relationships between cells, termed as the graph autoencoder module. To mitigate the oversmoothing issue in GCNs, we introduce a ZINB-based autoencoder module that extracts content information from the data and learns latent representations of gene expression. These modules are further integrated through an attention fusion mechanism, ensuring effective combination of gene expression and structural information at each layer of the GCN. Additionally, a self-supervised learning module is incorporated to enhance the robustness of the learned embeddings. Extensive experiments demonstrate that scASDC outperforms existing state-of-the-art methods, providing a robust and effective solution for single-cell clustering tasks. Our method paves the way for more accurate and meaningful analysis of single-cell RNA sequencing data, contributing to better understanding of cellular heterogeneity and biological processes. All code and public datasets used in this paper are available at \url{https://github.com/wenwenmin/scASDC} and \url{https://zenodo.org/records/12814320}.

Parallel Algorithms for Median Consensus Clustering in Complex Networks

We develop an algorithm that finds the consensus of many different clustering solutions of a graph. We formulate the problem as a median set partitioning problem and propose a greedy optimization technique. Unlike other approaches that find median set partitions, our algorithm takes graph structure into account and finds a comparable quality solution much faster than the other approaches. For graphs with known communities, our consensus partition captures the actual community structure more accurately than alternative approaches. To make it applicable to large graphs, we remove sequential dependencies from our algorithm and design a parallel algorithm. Our parallel algorithm achieves 35x speedup when utilizing 64 processing cores for large real-world graphs from single-cell experiments.

scGHSOM: Hierarchical clustering and visualization of single-cell and CRISPR data using growing hierarchical SOM

High-dimensional single-cell data poses significant challenges in identifying underlying biological patterns due to the complexity and heterogeneity of cellular states. We propose a comprehensive gene-cell dependency visualization via unsupervised clustering, Growing Hierarchical Self-Organizing Map (GHSOM), specifically designed for analyzing high-dimensional single-cell data like single-cell sequencing and CRISPR screens. GHSOM is applied to cluster samples in a hierarchical structure such that the self-growth structure of clusters satisfies the required variations between and within. We propose a novel Significant Attributes Identification Algorithm to identify features that distinguish clusters. This algorithm pinpoints attributes with minimal variation within a cluster but substantial variation between clusters. These key attributes can then be used for targeted data retrieval and downstream analysis. Furthermore, we present two innovative visualization tools: Cluster Feature Map and Cluster Distribution Map. The Cluster Feature Map highlights the distribution of specific features across the hierarchical structure of GHSOM clusters. This allows for rapid visual assessment of cluster uniqueness based on chosen features. The Cluster Distribution Map depicts leaf clusters as circles on the GHSOM grid, with circle size reflecting cluster data size and color customizable to visualize features like cell type or other attributes. We apply our analysis to three single-cell datasets and one CRISPR dataset (cell-gene database) and evaluate clustering methods with internal and external CH and ARI scores. GHSOM performs well, being the best performer in internal evaluation (CH=4.2). In external evaluation, GHSOM has the third-best performance of all methods.

Transformer-based Single-Cell Language Model: A Survey

The transformers have achieved significant accomplishments in the natural language processing as its outstanding parallel processing capabilities and highly flexible attention mechanism. In addition, increasing studies based on transformers have been proposed to model single-cell data. In this review, we attempt to systematically summarize the single-cell language models and applications based on transformers. First, we provide a detailed introduction about the structure and principles of transformers. Then, we review the single-cell language models and large language models for single-cell data analysis. Moreover, we explore the datasets and applications of single-cell language models in downstream tasks such as batch correction, cell clustering, cell type annotation, gene regulatory network inference and perturbation response. Further, we discuss the challenges of single-cell language models and provide promising research directions. We hope this review will serve as an up-to-date reference for researchers interested in the direction of single-cell language models.