A simple high-throughput approach identifies actionable drug sensitivities in patient-derived tumor organoids, bioRxiv, 2017-06-29
AbstractThere is increasing interest in developing 3D tumor organoid models for drug development and personalized medicine applications. While tumor organoids are in principle amenable to high-throughput drug screenings, progress has been hampered by technical constraints and extensive manipulations required by current methodologies. Here, we introduce a miniaturized, fully automatable, flexible high-throughput method using a simplified geometry to rapidly establish 3D organoids from cell lines and primary tissue and robustly assay drug responses. As proof of principle, we use our miniring approach to establish organoids of high-grade serous tumors and one carcinosarcoma of the ovaries and screen hundreds of protein kinase compounds currently FDA-approved or in clinical development. In all cases we could identify drugs causing significant reduction in cell viability, number and size of organoids within a week from surgery, a timeline compatible with therapeutic decision making.
biorxiv cancer-biology 0-100-users 2017Chromatin accessibility dynamics of myogenesis at single cell resolution, bioRxiv, 2017-06-27
AbstractOver a million DNA regulatory elements have been cataloged in the human genome, but linking these elements to the genes that they regulate remains challenging. We introduce Cicero, a statistical method that connects regulatory elements to target genes using single cell chromatin accessibility data. We apply Cicero to investigate how thousands of dynamically accessible elements orchestrate gene regulation in differentiating myoblasts. Groups of co-accessible regulatory elements linked by Cicero meet criteria of “chromatin hubs”, in that they are physically proximal, interact with a common set of transcription factors, and undergo coordinated changes in histone marks that are predictive of gene expression. Pseudotemporal analysis revealed a subset of elements bound by MYOD in myoblasts that exhibit early opening, potentially serving as the initial sites of recruitment of chromatin remodeling and histone-modifying enzymes. The methodological framework described here constitutes a powerful new approach for elucidating the architecture, grammar and mechanisms of cis-regulation on a genome-wide basis.
biorxiv genomics 100-200-users 2017General sexual desire, but not desire for uncommitted sexual relationships, tracks changes in women’s hormonal status, bioRxiv, 2017-06-27
AbstractSeveral recent longitudinal studies have investigated the hormonal correlates of both young adult women’s general sexual desire and, more specifically, their desire for uncommitted sexual relationships. Findings across these studies have been mixed, potentially because each study tested only small samples of women (Ns = 43, 33, and 14). Here we report results from a much larger (N = 375) longitudinal study of hormonal correlates of young adult women’s general sexual desire and their desire for uncommitted sexual relationships. Our analyses suggest that within-woman changes in general sexual desire are negatively related to progesterone, but are not related to testosterone or cortisol. We observed some positive relationships for estradiol, but these were generally only significant for solitary sexual desire. By contrast with our results for general sexual desire, analyses showed no evidence that changes in women’s desire for uncommitted sexual relationships are related to their hormonal status. Together, these results suggest that changes in hormonal status contribute to changes in women’s general sexual desire, but do not influence women’s desire for uncommitted sexual relationships.
biorxiv animal-behavior-and-cognition 100-200-users 2017Evaluating Metagenome Assembly on a Simple Defined Community with Many Strain Variants, bioRxiv, 2017-06-26
AbstractWe evaluate the performance of three metagenome assemblers, IDBA, MetaSPAdes, and MEGAHIT, on short-read sequencing of a defined “mock” community containing 64 genomes (Shakya et al. (2013)). We update the reference metagenome for this mock community and detect several additional genomes in the read data set. We show that strain confusion results in significant loss in assembly of reference genomes that are otherwise completely present in the read data set. In agreement with previous studies, we find that MEGAHIT performs best computationally; we also show that MEGAHIT tends to recover larger portions of the strain variants than the other assemblers.
biorxiv bioinformatics 100-200-users 2017Corrigendum and follow-up Whole genome sequencing of multiple CRISPR-edited mouse lines suggests no excess mutations, bioRxiv, 2017-06-24
Our previous publication suggested CRISPR-Cas9 editing at the zygotic stage might unexpectedly introduce a multitude of subtle but unintended mutations, an interpretation that not surprisingly raised numerous questions. The key issue is that since parental lines were not available, might the reported variants have been inherited? To expand upon the limited available whole genome data on whether CRISPR-edited mice show more genetic variation, whole-genome sequencing was performed on two other mouse lines that had undergone a CRISPR-editing procedure. Again, parents were not available for either the Capn5 nor Fblim1 CRISPR-edited mouse lines, so strain controls were examined. Additionally, we also include verification of variants detected in the initial mouse line. Taken together, these whole-genome-sequencing-level results support the idea that in specific cases, CRISPR-Cas9 editing can precisely edit the genome at the organismal level and may not introduce numerous, unintended, off-target mutations.
biorxiv bioengineering 200-500-users 2017A Guide to Robust Statistical Methods in Neuroscience, bioRxiv, 2017-06-21
ABSTRACTThere is a vast array of new and improved methods for comparing groups and studying associations that offer the potential for substantially increasing power, providing improved control over the probability of a Type I error, and yielding a deeper and more nuanced understanding of neuroscience data. These new techniques effectively deal with four insights into when and why conventional methods can be unsatisfactory. But for the non-statistician, the vast array of new and improved techniques for comparing groups and studying associations can seem daunting, simply because there are so many new methods that are now available. The paper briefly reviews when and why conventional methods can have relatively low power and yield misleading results. The main goal is to suggest some general guidelines regarding when, how and why certain modern techniques might be used.
biorxiv neuroscience 200-500-users 2017