Perception of naturally dead conspecifics impairs health and longevity through serotonin signaling in Drosophila, bioRxiv, 2019-01-09
Sensory perception modulates health and aging across taxa. Understanding the nature of relevant cues and the mechanisms underlying their action may lead to novel interventions that improve the length and quality of life. In humans, psychological trauma is often associated with the recognition of dead individuals, with chronic exposure leading to persistent mental health issues including depression and post-traumatic stress disorder. The mechanisms that link mental and physical health, and the degree to which these are shared across species, remain largely unknown. Here we show that the vinegar fly, Drosophila melanogaster, has the capability to perceive dead conspecifics in its environment and that this perceptive experience induces both short- and long-term effects on health and longevity. Death perception is mediated by visual and olfactory cues, and remarkably, its effects on aging are eliminated by targeted attenuation of serotonin signaling. Our results suggest a complex perceptive ability in Drosophila that reveals deeply conserved mechanistic links between psychological state and aging, the roots of which might be unearthed using invertebrate model systems.
biorxiv animal-behavior-and-cognition 100-200-users 2019Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval. Supplementary Methods And Results, bioRxiv, 2019-01-08
Despite strong vetting for disease activity, only 10% of candidate new molecular entities in early stage clinical trials are eventually approved. Analyzing historical pipeline data, Nelson et al. 2015 (Nat. Genet.) concluded pipeline drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. Taking advantage of recent clinical development advances and rapid growth in GWAS datasets, we extend the original work using updated data, test whether genetic evidence predicts future successes and introduce statistical models adjusting for target and indication-level properties. Our work confirms drugs with genetically supported targets were more likely to be successful in Phases II and III. When causal genes are clear (Mendelian traits and GWAS associations linked to coding variants), we find the use of human genetic evidence increases approval from Phase I by greater than two-fold, and, for Mendelian associations, the positive association holds prospectively. Our findings suggest investments into genomics and genetics are likely to be beneficial to companies deploying this strategy.
biorxiv genetics 100-200-users 2019Microtubule plus-end dynamics link wound repair to the innate immune response, bioRxiv, 2019-01-07
As a first line of defence against the environment, the epidermis protect animals from infection and physical damage. In C. elegans, wounding the epidermal epithelium triggers both an immune reaction and a repair response. Exactly how these are controlled, and the degree to which they are inter-connected remains unclear. To address these questions, we established a simple system for simultaneously inflicting precise laser wounds and imaging at high spatial and temporal resolution. We show that in C. elegans, wounding provokes a rapid sealing of the plasma membrane, involving reorganisation of phosphatidylinositol 4,5-bisphosphate domains. This is followed by a radial recruitment at the wound site of EBP-2EB1, a protein that binds the plus ends of microtubules. EB1 recruitment is accompanied by a reorganisation of microtubules, required for the subsequent recruitment of actin and wound closure. It is also required for the directed trafficking towards the site of injury of the key signaling protein SNF-12. In the absence of SNF-12 recruitment, there is an abrogation of the immune response. Our results suggest that microtubule dynamics coordinate the cytoskeletal changes required for wound repair and the concomitant activation of the innate immune response.
biorxiv cell-biology 100-200-users 2019GToTree a user-friendly workflow for phylogenomics, bioRxiv, 2019-01-06
Genome-level evolutionary inference (i.e., phylogenomics) is becoming an increasingly essential step in many biologists' work - such as in the characterization of newly recovered genomes, or in leveraging available reference genomes to guide evolutionary questions. Accordingly, there are several tools available for the major steps in a phylogenomics workflow. But for the biologist whose main focus is not bioinformatics, much of the computational work required - such as accessing genomic data on large scales, integrating genomes from different file formats, performing required filtering, stitching different tools together, etc. - can be prohibitive. Here I introduce GToTree, a command-line tool that can take any combination of fasta files, GenBank files, andor NCBI assembly accessions as input and outputs an alignment file, estimates of genome completeness and redundancy, and a phylogenomic tree based on the specified single-copy gene (SCG) set. While GToTree can work with any custom hidden Markov Models (HMMs), also included are 13 newly generated SCG-set HMMs for different lineages and levels of resolution, built based on searches of ~12,000 bacterial and archaeal high-quality genomes. GToTree aims to give more researchers the capability to make phylogenomic trees.
biorxiv bioinformatics 100-200-users 2019A pitfall for machine learning methods aiming to predict across cell types, bioRxiv, 2019-01-05
AbstractMachine learning models used to predict phenomena such as gene expression, enhancer activity, transcription factor binding, or chromatin conformation are most useful when they can generalize to make accurate predictions across cell types. In this situation, a natural strategy is to train the model on experimental data from some cell types and evaluate performance on one or more held-out cell types. In this work, we show that when the training set contains examples derived from the same genomic loci across multiple cell types, the resulting model can be susceptible to a particular form of bias related to memorizing the average activity associated with each genomic locus. Consequently, the trained model may appear to perform well when evaluated on the genomic loci that it was trained on but tends to perform poorly on loci that it was not trained on. We demonstrate this phenomenon by using epigenomic measurements and nucleotide sequence to predict gene expression and chromatin domain boundaries, and we suggest methods to diagnose and avoid the pitfall. We anticipate that, as more data and computing resources become available, future projects will increasingly risk suffering from this issue.
biorxiv bioinformatics 100-200-users 2019General visual and contingent thermal cues interact to elicit attraction in female Aedes aegypti mosquitoes, bioRxiv, 2019-01-03
Female Aedes aegypti mosquitoes use multiple sensory modalities to hunt human hosts to obtain a blood-meal for egg production. Attractive cues include carbon dioxide (CO2), a major component of exhaled breath [1, 2]; heat elevated above ambient temperature, signifying warm-blooded skin [3, 4]; and dark visual contrast [5, 6], proposed to bridge long-range olfactory and short-range thermal cues [7]. Any of these sensory cues in isolation is an incomplete signal of a human host, and so a mosquito must integrate multi-modal sensory information before committing to approaching and biting a person [8]. Here, we study the interaction of visual cues, heat, and CO2 to investigate the contributions of human-associated stimuli to host-seeking decisions. We show that tethered flying mosquitoes strongly orient toward dark visual contrast regardless of CO2 stimulation and internal host-seeking status. This suggests that attraction to visual contrast is general, and not contingent on other host cues. In free-flight experiments with CO2, adding a dark contrasting visual cue to a warmed surface enhanced host-seeking. Moderate warmth became more attractive to mosquitoes, and mosquitoes aggregated on the cue at all non-noxious temperatures. Gr3 mutants, unable to detect CO2, were lured to the visual cue at ambient temperatures, but fled and did not return when the surface was warmed to host-like temperatures. This suggests that attraction to thermal cues is contingent on the presence of the additional human sensory cue CO2. Our results illustrate that mosquitoes integrate general attractive visual stimuli with the context-dependent thermal stimuli to seek promising sites for blood-feeding.
biorxiv neuroscience 100-200-users 2019