Live Mouse Tracker real-time behavioral analysis of groups of mice, bioRxiv, 2018-06-14

Preclinical studies of psychiatric disorders require the use of animal models to investigate the impact of environmental factors or genetic mutations on complex traits such as decision-making and social interactions. Here, we present a real-time method for behavior analysis of mice housed in groups that couples computer vision, machine learning and Triggered-RFID identification to track and monitor animals over several days in enriched environments. The system extracts a thorough list of individual and collective behavioral traits and provides a unique phenotypic profile for each animal. On mouse models, we study the impact of mutations of genes Shank2 and Shank3 involved in autism. Characterization and integration of data from behavioral profiles of mutated female mice reveals distinctive activity levels and involvement in complex social configuration.

biorxiv animal-behavior-and-cognition 100-200-users 2018

Adversarial childhood events are associated with Sudden Infant Death Syndrome (SIDS) an ecological study, bioRxiv, 2018-06-07

AbstractSudden Infant Death Syndrome (SIDS) is the most common cause of postneonatal infant death. The allostatic load hypothesis posits that SIDS is the result of perinatal cumulative painful, stressful, or traumatic exposures that tax neonatal regulatory systems. To test it, we explored the relationships between SIDS and two common stressors, male neonatal circumcision (MNC) and prematurity, using latitudinal data from 15 countries and over 40 US states during the years 1999-2016. We used linear regression analyses and likelihood ratio tests to calculate the association between SIDS and the stressors. SIDS prevalence was significantly and positively correlated with MNC and prematurity rates. MNC explained 14.2% of the variability of SIDS’s male bias in the US, reminiscent of the Jewish myth of Lilith, the killer of infant males. Combined, the stressors increased the likelihood of SIDS. Ecological analyses are useful to generate hypotheses but cannot provide strong evidence of causality. Biological plausibility is provided by a growing body of experimental and clinical evidence linking adversary preterm and early-life events with SIDS. Together with historical evidence, our findings emphasize the necessity of cohort studies that consider these environmental stressors with the aim of improving the identification of at-risk infants and reducing infant mortality.

biorxiv pathology 100-200-users 2018

Toward machine-guided design of proteins, bioRxiv, 2018-06-02

AbstractProteins—molecular machines that underpin all biological life—are of significant therapeutic and industrial value. Directed evolution is a high-throughput experimental approach for improving protein function, but has difficulty escaping local maxima in the fitness landscape. Here, we investigate how supervised learning in a closed loop with DNA synthesis and high-throughput screening can be used to improve protein design. Using the green fluorescent protein (GFP) as an illustrative example, we demonstrate the opportunities and challenges of generating training datasets conducive to selecting strongly generalizing models. With prospectively designed wet lab experiments, we then validate that these models can generalize to unseen regions of the fitness landscape, even when constrained to explore combinations of non-trivial mutations. Taken together, this suggests a hybrid optimization strategy for protein design in which a predictive model is used to explore difficult-to-access but promising regions of the fitness landscape that directed evolution can then exploit at scale.

biorxiv synthetic-biology 100-200-users 2018

Alevin efficiently estimates accurate gene abundances from dscRNA-seq data, bioRxiv, 2018-06-01

AbstractWe introduce alevin, a fast end-to-end pipeline to process droplet-based single cell RNA sequencing data, which performs cell barcode detection, read mapping, unique molecular identifier deduplication, gene count estimation, and cell barcode whitelisting. Alevin’s approach to UMI deduplication accounts for both gene-unique reads and reads that multimap between genes. This addresses the inherent bias in existing tools which discard gene-ambiguous reads, and improves the accuracy of gene abundance estimates.

biorxiv bioinformatics 100-200-users 2018

A genetically encoded fluorescent sensor for in vivo imaging of GABA, bioRxiv, 2018-05-15

AbstractCurrent techniques for monitoring GABA, the primary inhibitory neurotransmitter in vertebrates, cannot follow ephemeral transients in intact neural circuits. We applied the design principles used to create iGluSnFR, a fluorescent reporter of synaptic glutamate, to develop a GABA sensor using a protein derived from a previously unsequenced Pseudomonas fluorescens strain. Structure-guided mutagenesis and library screening led to a usable iGABASnFR (ΔFFmax ~ 2.5, Kd ~ 9 μM, good specificity, adequate kinetics). iGABASnFR is genetically encoded, detects single action potential-evoked GABA release events in culture, and produces readily detectable fluorescence increases in vivo in mice and zebrafish. iGABASnFR enabled tracking of (1) mitochondrial GABA content and its modulation by an anticonvulsant; (2) swimming-evoked GABAergic transmission in zebrafish cerebellum; (3) GABA release events during inter-ictal spikes and seizures in awake mice; and (4) GABAergic tone decreases during isoflurane anesthesia. iGABASnFR will permit high spatiotemporal resolution of GABA signaling in intact preparations.

biorxiv neuroscience 100-200-users 2018

The Repertoire of Mutational Signatures in Human Cancer, bioRxiv, 2018-05-15

ABSTRACTSomatic mutations in cancer genomes are caused by multiple mutational processes each of which generates a characteristic mutational signature. Using 84,729,690 somatic mutations from 4,645 whole cancer genome and 19,184 exome sequences encompassing most cancer types we characterised 49 single base substitution, 11 doublet base substitution, four clustered base substitution, and 17 small insertion and deletion mutational signatures. The substantial dataset size compared to previous analyses enabled discovery of new signatures, separation of overlapping signatures and decomposition of signatures into components that may represent associated, but distinct, DNA damage, repair andor replication mechanisms. Estimation of the contribution of each signature to the mutational catalogues of individual cancer genomes revealed associations with exogenous and endogenous exposures and defective DNA maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes contributing to the development of human cancer including a comprehensive reference set of mutational signatures in human cancer.

biorxiv cancer-biology 100-200-users 2018