Pan-cancer whole genome analyses of metastatic solid tumors, bioRxiv, 2018-09-21
AbstractMetastatic cancer is one of the major causes of death and is associated with poor treatment efficiency. A better understanding of the characteristics of late stage cancer is required to help tailor personalised treatment, reduce overtreatment and improve outcomes. Here we describe the largest pan-cancer study of metastatic solid tumor genomes, including 2,520 whole genome-sequenced tumor-normal pairs, analyzed at a median depth of 106x and 38x respectively, and surveying over 70 million somatic variants. Metastatic lesions were found to be very diverse, with mutation characteristics reflecting those of the primary tumor types, although with high rates of whole genome duplication events (56%). Metastatic lesions are relatively homogeneous with the vast majority (96%) of driver mutations being clonal and up to 80% of tumor suppressor genes bi-allelically inactivated through different mutational mechanisms. For 62% of all patients, genetic variants that may be associated with outcome of approved or experimental therapies were detected. These actionable events were distributed across various mutation types underlining the importance of comprehensive genomic tumor profiling for cancer precision medicine.
biorxiv cancer-biology 100-200-users 2018BRICseq bridges brain-wide interregional connectivity to neural activity and gene expression in single animals, bioRxiv, 2018-09-20
SummaryComprehensive analysis of neuronal networks requires brain-wide measurement of connectivity, activity, and gene expression. Although high-throughput methods are available for mapping brain-wide activity and transcriptomes, comparable methods for mapping region-to-region connectivity remain slow and expensive because they require averaging across hundreds of brains. Here we describe BRICseq, which leverages DNA barcoding and sequencing to map connectivity from single individuals in a few weeks and at low cost. Applying BRICseq to the mouse neocortex, we find that region-to-region connectivity provides a simple bridge relating transcriptome to activity The spatial expression patterns of a few genes predict region-to-region connectivity, and connectivity predicts activity correlations. We also exploited BRICseq to map the mutant BTBR mouse brain, which lacks a corpus callosum, and recapitulated its known connectopathies. BRICseq allows individual laboratories to compare how age, sex, environment, genetics and species affect neuronal wiring, and to integrate these with functional activity and gene expression.
biorxiv neuroscience 100-200-users 2018High-throughput mapping of mesoscale connectomes in individual mice, bioRxiv, 2018-09-20
AbstractBrain function is determined by connectivity among brain areas, and disruption of this connectivity leads to neuropsychiatric disorders. Understanding connectivity is essential to modern neuroscience, but mesoscale connectivity atlases are currently slow and expensive to generate, exist for few model systems, and require pooling across many brains. Here we present a method, muMAPseq (multisource Multiplexed Analysis of Projections by sequencing), which leverages barcoding and high-throughput sequencing to generate atlases from single animals rapidly and at low cost. We apply muMAPseq to tracing the neocortical connectome of individual mice, and demonstrate high reproducibility, and accuracy. Applying muMAPseq to the mutant BTBR mouse strain, which lacks a corpus callosum, we recapitulate its known connectopathies, and also uncover novel deficits. muMAPseq allows individual laboratories to generate atlases tailored to individuals, disease models, and new model species, and will facilitate quantitative comparative connectomics, permitting examination of how age, sex, environment, genetics and species affect neuronal wiring.
biorxiv neuroscience 100-200-users 2018Proximity sensors reveal social information transfer in maternity colonies of Common noctule bats, bioRxiv, 2018-09-20
Summary<jatslist list-type=order><jatslist-item>Bats are a highly gregarious taxon suggesting that social information should be readily available for making decision. Social information transfer in maternity colonies might be a particularly efficient mechanism for naïve pups to acquire information on resources from informed adults. However, such behaviour is difficult to study in the wild, in particular in elusive and small-bodied animals such as bats.<jatslist-item><jatslist-item>The goal of this study was to investigate the role of social information in acquiring access to two types of resources, which are crucial in the life of a juvenile bat suitable roosting sites and fruitful feeding grounds. We hypothesized that fledging offspring will make use of social information by following informed members of the social groups to unknown roosts or foraging sites.<jatslist-item><jatslist-item>In the present study we applied for the first time the newly developed miniaturized proximity sensor system ‘BATS’, a fully automated system for documenting associations among individual bats both while roosting and while on the wing. We quantified associations among juveniles and other group member while switching roosts and during foraging.<jatslist-item><jatslist-item>We found clear evidence for information transfer while switching roosts, mainly among juveniles and their genetically identified mothers. Anecdotal observations suggest intentional guidance behaviour by mothers, indicated by repeated commuting flights among the pup and the target roost. Infrequent, short meetings with colony members other than the mother indicate local enhancement at foraging sites, but no intentional information transfer.<jatslist-item><jatslist-item>Our study illustrates how advances in technology enable researchers to solve long-standing puzzles. Miniaturized proximity sensors facilitate the automated collection of continuous data sets and represent an ideal tool to gain novel insights into the sociobiology of elusive and small-bodied species.<jatslist-item>
biorxiv animal-behavior-and-cognition 0-100-users 2018A non-spatial account of place and grid cells based on clustering models of concept learning, bioRxiv, 2018-09-19
ABSTRACTOne view is that conceptual knowledge is organized using the circuitry in the medial temporal lobe (MTL) that supports spatial processing and navigation. In contrast, we find that a domain-general learning algorithm explains key findings in both spatial and conceptual domains. When the clustering model is applied to spatial navigation tasks, so called place and grid cell-like representations emerge because of the relatively uniform distribution of possible inputs in these tasks. The same mechanism applied to conceptual tasks, where the overall space can be higher-dimensional and sampling sparser, leads to representations more aligned with human conceptual knowledge. Although the types of memory supported by the MTL are superficially dissimilar, the information processing steps appear shared. Our account suggests that the MTL uses a general-purpose algorithm to learn and organize context-relevant information in a useful format, rather than relying on navigation-specific neural circuitry.
biorxiv neuroscience 100-200-users 2018Integrin-mediated attachment of the blastoderm to the vitelline envelope impacts gastrulation of insects, bioRxiv, 2018-09-19
AbstractDuring gastrulation, physical forces reshape the simple embryonic tissue to form a complex body plan of multicellular organisms1. These forces often cause large-scale asymmetric movements of the embryonic tissue2,3. In many embryos, the tissue undergoing gastrulation movements is surrounded by a rigid protective shell4,5. While it is well recognized that gastrulation movements depend on forces generated by tissue-intrinsic contractility6,7, it is not known if interactions between the tissue and the protective shell provide additional forces that impact gastrulation. Here we show that a particular part of the blastoderm tissue of the red flour beetle Tribolium castaneum tightly adheres in a temporally coordinated manner to the vitelline envelope surrounding the embryo. This attachment generates an additional force that counteracts the tissue-intrinsic contractile forces to create asymmetric tissue movements. Furthermore, this localized attachment is mediated by a specific integrin, and its knock-down leads to a gastrulation phenotype consistent with complete loss of attachment. Moreover, analysis of another integrin in the fruit fly Drosophila melanogaster suggests that gastrulation in this organism also relies on adhesion between the blastoderm and the vitelline. Together, our findings reveal a conserved mechanism whereby the spatiotemporal pattern of tissue adhesion to the vitelline envelope provides controllable counter-forces that shape gastrulation movements in insects.
biorxiv developmental-biology 100-200-users 2018