A comprehensive comparison on cell-type composition inference for spatial transcriptomics data.

Spatial transcriptomics (ST) technologies allow researchers to examine transcriptional profiles along with maintained positional information. Such spatially resolved transcriptional characterization of intact tissue samples provides an integrated view of gene expression in its natural spatial and functional context. However, high-throughput sequencing-based ST technologies cannot yet reach single cell resolution. Thus, similar to bulk RNA-seq data, gene expression data at ST spot-level reflect transcriptional profiles of multiple cells and entail the inference of cell-type composition within each ST spot for valid and powerful subsequent analyses. Realizing the critical importance of cell-type decomposition, multiple groups have developed ST deconvolution methods. The aim of this work is to review state-of-the-art methods for ST deconvolution, comparing their strengths and weaknesses. In particular, we construct ST spots from single-cell level ST data to assess the performance of 10 methods, with either ideal reference or non-ideal reference. Furthermore, we examine the performance of these methods on spot- and bead-level ST data by comparing estimated cell-type proportions to carefully matched single-cell ST data. In comparing the performance on various tissues and technological platforms, we concluded that RCTD and stereoscope achieve more robust and accurate inferences.

Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity.

Aberrant cell-cycle activity and DNA damage are emerging as important pathological components in various neurodegenerative conditions. However, their underlying mechanisms are poorly understood. Here, we show that deregulation of histone deacetylase 1 (HDAC1) activity by p25/Cdk5 induces aberrant cell-cycle activity and double-strand DNA breaks leading to neurotoxicity. In a transgenic model for neurodegeneration, p25/Cdk5 activity elicited cell-cycle activity and double-strand DNA breaks that preceded neuronal death. Inhibition of HDAC1 activity by p25/Cdk5 was identified as an underlying mechanism for these events, and HDAC1 gain of function provided potent protection against DNA damage and neurotoxicity in cultured neurons and an in vivo model for ischemia. Our findings outline a pathological signaling pathway illustrating the importance of maintaining HDAC1 activity in the adult neuron. This pathway constitutes a molecular link between aberrant cell-cycle activity and DNA damage and is a potential target for therapeutics against diseases and conditions involving neuronal death.