Modelling capture efficiency of single-cell RNA-sequencing data improves inference of transcriptome-wide burst kinetics

MOTIVATION: Gene expression is characterised by stochastic bursts of transcription that occur at brief and random periods of promoter activity. The kinetics of gene expression burstiness differs across the genome and is dependent on the promoter sequence, among other factors. Single-cell RNA sequencing (scRNA-seq) has made it possible to quantify the cell-to-cell variability in transcription at a global genome-wide level. However, scRNA-seq data is prone to technical variability, including low and variable capture efficiency of transcripts from individual cells. RESULTS: Here, we propose a novel mathematical theory for the observed variability in scRNA-seq data. Our method captures burst kinetics and variability in both the cell size and capture efficiency, which allows us to propose several likelihood-based and simulation-based methods for the inference of burst kinetics from scRNA-seq data. Using both synthetic and real data, we show that the simulation-based methods provide an accurate, robust and flexible tool for inferring burst kinetics from scRNA-seq data. In particular, in a supervised manner, a simulation-based inference method based on neural networks proves to be accurate and useful when applied to both allele and non-allele-specific scRNA-seq data. AVAILABILITY: The code for Neural Network and Approximate Bayesian Computation inference is available at https://github.com/WT215/nnRNA and https://github.com/WT215/Julia_ABC respectively. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online

Le Togo sous drapeau allemand (1894-1897)

Pendant trois ans, de 1894 à 1897, Heinrich Klose a arpenté le Togo, de la côte au nord, au moment de la mise en place de l'autorité allemande. Il observe avec acuité les paysages et les hommes, les cultures et les coutumes. L'auteur décrit minutieusement trois grandes régions : 1) Lomé, la côte et le lac Togo, 2) l'itinéraire de Lomé au sud des Monts du Togo (Kpalimé, Agou, Misahohé, Kpandu), 3) le pays bassar, où Klose séjourne longuement, et une expédition jusqu'à Djougou à travers le Nord-Togo d'aujourd'hui. (Résumé de l'éditeur

Diet suppresses glioblastoma initiation in mice by maintaining quiescence of mutation-bearing neural stem cells

Glioblastoma is thought to originate from neural stem cells (NSCs) of the subventricular zone that acquire genetic alterations. In the adult brain, NSCs are largely quiescent, suggesting that deregulation of quiescence maintenance may be a prerequisite for tumor initiation. Although inactivation of the tumor suppressor p53 is a frequent event in gliomagenesis, whether or how it affects quiescent NSCs (qNSCs) remains unclear. Here, we show that p53 maintains quiescence by inducing fatty-acid oxidation (FAO) and that acute p53 deletion in qNSCs results in their premature activation to a proliferative state. Mechanistically, this occurs through direct transcriptional induction of PPARGC1a, which in turn activates PPARα to upregulate FAO genes. Dietary supplementation with fish oil containing omega-3 fatty acids, natural PPARα ligands, fully restores quiescence of p53-deficient NSCs and delays tumor initiation in a glioblastoma mouse model. Thus, diet can silence glioblastoma driver mutations, with important implications for cancer prevention

Slow violence and toxic geographies : ‘out of sight’ to whom?

Toxic pollution is a form of violence. This article explores the gradual brutalities that communities surrounded by petrochemical infrastructure endure over time. Contributing to political geographies of violence and environmental justice, this paper puts the concept of ‘slow violence’ into critical comparison with work on ‘structural violence’. In doing so, the paper makes two key contributions: First, it emphasizes the intimate connections between structural and slow forms of harm, arguing that structural inequality can mutate into noxious instances of slow violence. Second, the paper pushes back against framings of toxic landscapes as entirely invisible to the people they impact. Instead of accepting the standard definition of slow violence as ‘out of sight’, we have to instead ask the question: ‘out of sight to whom?’ In asking this question, and taking seriously the knowledge claims of communities who inhabit toxic spaces, we can begin to unravel the political structures that sustain the uneven geographies of pollution. Based on long-term ethnographic research in a postcolonial region of Louisiana, nicknamed ‘Cancer Alley’, this paper reveals how people gradually ‘witness’ the impacts of slow violence in their everyday lives. Finally, drawing on the notion of ‘epistemic violence’, the paper suggests that slow violence does not persist due to a lack of arresting stories about pollution, but because these stories do not count, thus rendering certain populations and geographies vulnerable to sacrifice

Glioblastoma cell fate is differentially regulated by the microenvironments of the tumor bulk and infiltrative margin

Glioblastoma (GBM) recurrence originates from invasive margin cells that escape surgical debulking, but to what extent these cells resemble their bulk counterparts remains unclear. Here, we generated three immunocompetent somatic GBM mouse models, driven by subtype-associated mutations, to compare matched bulk and margin cells. We find that, regardless of mutations, tumors converge on common sets of neural-like cellular states. However, bulk and margin have distinct biology. Injury-like programs associated with immune infiltration dominate in the bulk, leading to the generation of lowly proliferative injured neural progenitor-like cells (iNPCs). iNPCs account for a significant proportion of dormant GBM cells and are induced by interferon signaling within T cell niches. In contrast, developmental-like trajectories are favored within the immune-cold margin microenvironment resulting in differentiation toward invasive astrocyte-like cells. These findings suggest that the regional tumor microenvironment dominantly controls GBM cell fate and biological vulnerabilities identified in the bulk may not extend to the margin residuum

Cyclebase.org—a comprehensive multi-organism online database of cell-cycle experiments

The past decade has seen the publication of a large number of cell-cycle microarray studies and many more are in the pipeline. However, data from these experiments are not easy to access, combine and evaluate. We have developed a centralized database with an easy-to-use interface, Cyclebase.org, for viewing and downloading these data. The user interface facilitates searches for genes of interest as well as downloads of genome-wide results. Individual genes are displayed with graphs of expression profiles throughout the cell cycle from all available experiments. These expression profiles are normalized to a common timescale to enable inspection of the combined experimental evidence. Furthermore, state-of-the-art computational analyses provide key information on both individual experiments and combined datasets such as whether or not a gene is periodically expressed and, if so, the time of peak expression. Cyclebase is available at http://www.cyclebase.org

Protocol Dependence of Sequencing-Based Gene Expression Measurements

RNA Seq provides unparalleled levels of information about the transcriptome including precise expression levels over a wide dynamic range. It is essential to understand how technical variation impacts the quality and interpretability of results, how potential errors could be introduced by the protocol, how the source of RNA affects transcript detection, and how all of these variations can impact the conclusions drawn. Multiple human RNA samples were used to assess RNA fragmentation, RNA fractionation, cDNA synthesis, and single versus multiple tag counting. Though protocols employing polyA RNA selection generate the highest number of non-ribosomal reads and the most precise measurements for coding transcripts, such protocols were found to detect only a fraction of the non-ribosomal RNA in human cells. PolyA RNA excludes thousands of annotated and even more unannotated transcripts, resulting in an incomplete view of the transcriptome. Ribosomal-depleted RNA provides a more cost-effective method for generating complete transcriptome coverage. Expression measurements using single tag counting provided advantages for assessing gene expression and for detecting short RNAs relative to multi-read protocols. Detection of short RNAs was also hampered by RNA fragmentation. Thus, this work will help researchers choose from among a range of options when analyzing gene expression, each with its own advantages and disadvantages