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In the realm of transcriptional dynamics, understanding the intricate interplay of regulatory proteins is crucial for deciphering processes ranging from normal development to disease progression. However, traditional RNA velocity methods often overlook the underlying regulatory drivers of gene expression changes over time. This gap in knowledge hinders our ability to unravel the mechanistic intricacies of these dynamic processes. scKINETICs (Key regulatory Interaction NETwork for Inferring Cell Speed) (Burdziak et al, 2023) offers a dynamic model for gene expression changes that simultaneously learns per-cell transcriptional velocities and a governing gene regulatory network. By employing an expectation-maximization approach, scKINETICS quantifies the impact of each regulatory element on its target genes, incorporating insights from epigenetic data, gene-gene coexpression patterns and constraints dictated by the phenotypic manifold.

Mapping out the coarse-grained connectivity structures of complex manifolds Biological systems often change over time, as old cells die and new cells are created through differentiation from progenitor cells. This means that at any given time, not all cells will be at the same stage of development. In this sense, a single-cell sample could contain cells at different stages of differentiation. By analyzing the data, we can identify which cells are at which stages and build a model for their biological transitions. By quantifying the connectivity of partitions (groups, clusters) of the single-cell graph, partition-based graph abstraction (PAGA) generates a much simpler abstracted graph (PAGA graph) of partitions, in which edge weights represent confidence in the presence of connections. In this notebook, we will introduce the concept of single-cell Trajectory Analysis using PAGA (Partition-based graph abstraction) in the context of hematopoietic differentiation.

Power analyses are considered important factors in designing high-quality experiments. However, such analyses remain a challenge in single-cell RNA-seq studies due to the presence of hierarchical structure within the data (Zimmerman et al., 2021). As cells sampled from the same individual share genetic and environmental backgrounds, these cells are more correlated than cells sampled from different individuals. Currently, most power analyses and hypothesis tests (e.g., differential expression) in scRNA-seq data treat cells as if they were independent, thus ignoring the intra-sample correlation, which could lead to incorrect inferences. Hierarchicell (Zimmerman, K.D. and Langefeld, C.D., 2021) is an R package proposed to estimate power for testing hypotheses of differential expression in scRNA-seq data while considering the hierarchical correlation structure that exists in the data. The method offers four important categories of functions: data loading and cleaning, empirical estimation of distributions, simulating expression data, and computing type 1 error or power. In this notebook, we will illustrate an example workflow of Hierarchicell. The notebook is inspired by Hierarchicell's vignette and modified to demonstrate how the tool works on BioTuring's platform.

Computational methods that model how the gene expression of a cell is influenced by interacting cells are lacking. We present NicheNet, a method that predicts ligand–target links between interacting cells by combining their expression data with prior knowledge of signaling and gene regulatory networks. We applied NicheNet to the tumor and immune cell microenvironment data and demonstrated that NicheNet can infer active ligands and their gene regulatory effects on interacting cells.