Whole-genome sequencing of rare disease patients in a national healthcare system, bioRxiv, 2019-01-02
Most patients with hereditary rare diseases do not receive a molecular diagnosis and the aetiological variants and mediating genes for half such disorders remain to be discovered. We implemented whole-genome sequencing (WGS) in a national healthcare system to streamline diagnosis and to discover unknown aetiological variants, in the coding and non-coding regions of the genome. In a pilot study for the 100,000 Genomes Project, we generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,040 of the 7,065 patients with detailed phenotypic data. We identified 99 Mendelian associations between genes and rare diseases, of which at least 80 are confirmed aetiological. Using WGS of UK Biobank, we showed that rare alleles can explain the presence of some individuals in the tails of a quantitative red blood cell (RBC) trait 1. Finally, we reported novel non-coding variants which cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.
biorxiv genomics 200-500-users 2019Fundamental bounds on learning performance in neural circuits, bioRxiv, 2019-01-01
How does the size of a neural circuit influence its learning performance? Intuitively, we expect the learning capacity of a neural circuit to grow with the number of neurons and synapses. Larger brains tend to be found in species with higher cognitive function and learning ability. Similarly, adding connections and units to artificial neural networks can allow them to solve more complex tasks. However, we show that in a biologically relevant setting where synapses introduce an unavoidable amount of noise, there is an optimal size of network for a given task. Beneath this optimal size, our analysis shows how adding apparently redundant neurons and connections can make tasks more learnable. Therefore large neural circuits can either devote connectivity to generating complex behaviors, or exploit this connectivity to achieve faster and more precise learning of simpler behaviors. Above the optimal network size, the addition of neurons and synaptic connections starts to impede learning performance. This suggests that overall brain size may be constrained by the need to learn efficiently with unreliable synapses, and may explain why some neurological learning deficits are associated with hyperconnectivity. Our analysis is independent of specific learning rules and uncovers fundamental relationships between learning rate, task performance, network size and intrinsic noise in neural circuits.
biorxiv neuroscience 0-100-users 2019Loud music and the specific sound stress open the blood-brain barrier new fundamental, biomedical, and social aspects, bioRxiv, 2019-01-01
AbstractThe blood-brain barrier (BBB) poses a significant challenge for drug brain delivery. The limitation of our knowledge about the nature of BBB explains the slow progress in the therapy of brain diseases and absence of methods for drug brain delivery in the clinical practice.Here we show that BBB opens for lowhigh weight molecules and nanocarriers after exposure of loud musicsound of 90 dB and 100 dB (regardless its frequency) as being easily produced by MP3MP4 players, kitchen appliances, loudspeakers at concerts. The role of sound, sound-induced stress and molecular mechanisms behind is discussed in the framework of BBB opening as an informative platform for a novel fundamental knowledge about the nature of BBB and for the development of a non-invasive brain drug delivery technology.Social aspects of musicsound-induced opening of BBB provide completely new information about noise and healthy life conditions that will stimulate new research in this field.
biorxiv neuroscience 100-200-users 2019Flowers respond to pollinator sound within minutes by increasing nectar sugar concentration, bioRxiv, 2018-12-29
Can plants hear? That is, can they sense airborne sounds and respond to them? Here we show that Oenothera drummondii flowers, exposed to the playback sound of a flying bee or to synthetic sound-signals at similar frequencies, produced sweeter nectar within 3 minutes, potentially increasing the chances of cross pollination. We found that the flowers vibrated mechanically in response to these sounds, suggesting a plausible mechanism where the flower serves as the plant’s auditory sensory organ. Both the vibration and the nectar response were frequency-specific the flowers responded to pollinator sounds, but not to higher frequency sound. Our results document for the first time that plants can rapidly respond to pollinator sounds in an ecologically relevant way. Sensitivity of plants to pollinator sound can affect plant-pollinator interactions in a wide range of ways Plants could allocate their resources more adequately, focusing on the time of pollinator activity; pollinators would then be better rewarded per time unit; flower shape may be selected for its effect on hearing ability, and not only on signaling; and pollinators may evolve to make sounds that the flowers can hear. Finally, our results suggest that plants may be affected by other sounds as well, including antropogenic ones.
biorxiv ecology 500+-users 2018Highly multiplexed in situ protein imaging with signal amplification by Immuno-SABER, bioRxiv, 2018-12-29
AbstractProbing the molecular organization of tissues requires in situ analysis by microscopy. However current limitations in multiplexing, sensitivity, and throughput collectively constitute a major barrier for comprehensive single-cell profiling of proteins. Here, we report Immunostaining with Signal Amplification By Exchange Reaction (Immuno-SABER), a rapid, highly multiplexed signal amplification method that simultaneously tackles these key challenges. Immuno-SABER utilizes DNA-barcoded antibodies and provides a method for highly multiplexed signal amplification via modular orthogonal DNA concatemers generated by Primer Exchange Reaction. This approach offers the capability to preprogram and control the amplification level independently for multiple targets without in situ enzymatic reactions, and the intrinsic scalability to rapidly amplify and image a large number of protein targets. We validated our approach in diverse sample types including cultured cells, cryosections, FFPE sections, and whole mount tissues. We demonstrated independently tunable 5-180-fold amplification for multiple targets, covering the full signal range conventionally achieved by secondary antibodies to tyramide signal amplification, as well as simultaneous signal amplification for 10 different proteins using standard equipment and workflow. We further combined Immuno-SABER with Expansion Microscopy to enable rapid and highly multiplexed super-resolution tissue imaging. Overall, Immuno-SABER presents an effective and accessible platform for rapid, multiplexed imaging of proteins across scales with high sensitivity.
biorxiv cell-biology 200-500-users 2018Human microbiome aging clocks based on deep learning and tandem of permutation feature importance and accumulated local effects, bioRxiv, 2018-12-29
The human gut microbiome is a complex ecosystem that both affects and is affected by its host status. Previous analyses of gut microflora revealed associations between specific microbes and host health and disease status, genotype and diet. Here, we developed a method of predicting the biological age of the host based on the microbiological profiles of gut microbiota using a curated dataset of 1,165 healthy individuals (1,663 microbiome samples). Our predictive model, a human microbiome clock, has an architecture of a deep neural network and achieves the accuracy of 3.94 years mean absolute error in cross-validation. The performance of the deep microbiome clock was also evaluated on several additional populations. We further introduce a platform for biological interpretation of individual microbial features used in age models, which relies on permutation feature importance and accumulated local effects. This approach has allowed us to define two lists of 95 intestinal biomarkers of human aging. We further show that this list can be reduced to 39 taxa that convey the most information on their host's aging. Overall, we show that (a) microbiological profiles can be used to predict human age; and (b) microbial features selected by models are age-related.
biorxiv bioinformatics 200-500-users 2018