Biology subjects

Meyer, C.

Publications and source records attributed to Meyer, C..

49 records · Page 3Linked to original sources

bioRxiv2020

St. Jude Cloud a Pediatric Cancer Genomic Data Sharing Ecosystem

Effective data sharing is key to accelerating research that will improve the precision of diagnoses, efficacy of treatments and long-term survival of pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data sharing ecosystem developed via collaboration between St. Jude Childrens Research Hospital, DNAnexus, and Microsoft, for accessing, analyzing and visualizing genomic data from >10,000 pediatric cancer patients, long-term survivors of pediatric cancer and >800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabyes on St. Jude Cloud include 12,104 whole genomes, 7,697 whole exomes and 2,202 transcriptomes, which are freely available to researchers worldwide. The resource is expanding rapidly with regular data uploads from St. Judes prospective clinical genomics programs, providing public access as soon as possible rather than holding data back until publication. Three interconnected apps within the St. Jude Cloud ecosystem--Genomics Platform, Pediatric Cancer Knowledgebase (PeCan) and Visualization Community--provide a unique experience for simultaneously performing advanced data analysis in the cloud and enhancing the pediatric cancer knowledgebase. We demonstrate the value of the St. Jude Cloud ecosystem through use cases that classify 48 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 subtypes of pediatric cancer.

cancer biology↗

bioRxiv2020

Reducing ecological complexity using the archetype approach - an application to natural pest control

Natural control of crop pests has the potential to complement or replace intensive agricultural practices, but its mainstream application requires reliable predictions in diverse socioecological settings. In lack of a widely accepted model of natural pest control, we review existing modelling approaches and critically examine their potential to provide understanding and predictions across agricultural landscapes. Models that explicitly represent the underlying mechanisms are better positioned to represent the diversity and context sensitivity of natural pest control than correlative models. Such mechanistic models have used diverse techniques to represent crop-pest-enemy combinations at various spatiotemporal scales. However, certain regions of the world and socioeconomic aspects of natural pest control are underrepresented, while modelling approaches are restricted by a fundamental trade-off between generality and realism. We propose that modelling natural pest control across agroecosystems requires a framework of context-specific generalizations, based on empirical evidence and theoretical expectations. Reviewed models of natural pest control indicate potential attributes of such a general predictive framework.

ecology↗

bioRxiv2019

A clinically and genomically annotated nerve sheath tumor biospecimen repository.

Nerve sheath tumors occur as a heterogeneous group of neoplasms in patients with neurofibromatosis type 1 (NF1). The malignant form represents the most common cause of death in people with NF1, and even when benign, these tumors can result in significant disfigurement, neurologic dysfunction, and a range of profound symptoms. Lack of human tissue across the peripheral nerve tumors common in NF1 has been a major limitation in the development of new therapies. To address this unmet need, we have created an annotated collection of patient tumor samples, patient-derived cell lines, and patient-derived xenografts, and carried out high-throughput genomic and transcriptomic characterization to serve as a resource for further biologic and preclinical therapeutic studies. In this work, we release genomic and transcriptomic datasets comprised of 55 tumor samples derived from 23 individuals, complete with clinical annotation. All data are publicly available through the NF Data Portal and at http://synapse.org/jhubiobank.

cancer biology↗

bioRxiv2019

Differences in berry primary and secondary metabolisms identified by transcriptomic and metabolic profiling of two table grape color somatic variants

Anthocyanins are flavonoids responsible for the color of berries in skin-pigmented grapevine (Vitis vinifera L.). Due to the widely adopted vegetative propagation of this species, somatic mutations occurring in meristematic cell layers can be fixed and passed into the rest of the plant when cloned. In this study we focused on the transcriptomic and metabolic differences between two color somatic variants. Using microscopic, metabolic and mRNA profiling analyses we compared the table grape cultivar (cv.) Red Globe (RG, with purplish berry skin) and cv. Chimenti Globe (CG, with a contrasting reddish berry skin color). As expected, significant differences were found in the composition of flavonoids and other phenylpropanoids, but also in their upstream precursors shikimate and phenylalanine. Among primary metabolites, sugar phosphates related with sucrose biosynthesis were less accumulated in cv. CG. The red-skinned cv. CG only contained di-hydroxylated anthocyanins (i.e. peonidin and cyanidin) while the tri-hydroxylated derivatives malvidin, delphinidin and petunidin were absent, in correlation to the reddish cv. CG skin coloration. Transcriptomic analysis showed alteration in flavonoid metabolism and terpenoid pathways and in primary metabolism such as sugar content. Eleven flavonoid 35-hydroxylase gene copies were down-regulated in cv. CG. This family of cytochrome P450 oxidoreductases are key in the biosynthesis of tri-hydroxylated anthocyanins. Many transcription factors appeared down-regulated in cv. CG in correlation to the metabolic and transcriptomic changes observed. The use of molecular markers and its confirmation with our RNA-seq data showed the exclusive presence of the null MYBA2 white allele (i.e. homozygous in both L1 and L2 layers) in the two somatic variants. Therefore, the differences in MYBA1 expression seem sufficient for the skin pigmentation differences and the changes in MYBA target gene expression in cv. Chimenti Globe.

plant biology↗

bioRxiv2019

A cross-scale assessment of productivity-diversity relationships

AimBiodiversity and ecosystem productivity vary across the globe and considerable effort has been made to describe their relationships. Biodiversity-ecosystem functioning research has traditionally focused on how experimentally controlled species richness affects net primary productivity (S[->]NPP) at small spatial grains. In contrast, the influence of productivity on richness (NPP[->]S) has been explored at many grains in naturally assembled communities. Mismatches in spatial scale between approaches have fostered debate about the strength and direction of biodiversity-productivity relationships. Here we examine the direction and strength of productivitys influence on diversity (NPP[->]S) and of diversitys influence on productivity (S[->]NPP), and how this varies across spatial grains. Locationcontiguous USA Time period1999 - 2015 Major taxa studiedwoody species (angiosperms and gymnosperms) MethodsUsing data from North American forests at grains from local (672 m2) to coarse spatial units (median area = 35,677 km2), we assess relationships between diversity and productivity using structural equation and random forest models, while accounting for variation in climate, environmental heterogeneity, management, and forest age. ResultsWe show that relationships between S and NPP strengthen with spatial grain. Within each grain, S[->]NPP and NPP[->]S have similar magnitudes, meaning that processes underlying S[->]NPP and NPP[->]S either operate simultaneously, or that one of them is real and the other is an artifact. At all spatial grains, S was one of the weakest predictors of forest productivity, which was largely driven by biomass, temperature, and forest management and age. Main conclusionsWe conclude that spatial grain mediates relationships between biodiversity and productivity in real-world ecosystems and that results supporting predictions from each approach (NPP[->]S and S[->]NPP) serve as an impetus for future studies testing underlying mechanisms. Productivity-diversity relationships emerge at multiple spatial grains, which should widen the focus of national and global policy and research to larger spatial grains.

ecology↗

bioRxiv2019

Growing old too early, automated assessment of skeletal muscle single fiber biomechanics in ageing R349P desmin knock-in mice using the MyoRobot technology

Muscle biomechanics is determined by active motor-protein assembly and passive strain transmission through cytoskeletal structures. The extrasarcomeric desmin filament network aligns myofibrils at the z-discs, provides nuclear-sarcolemmal anchorage and may also serve as memory for muscle repositioning following large strains. Our previous analyses of R349P desmin knock-in mice, an animal model for the human R350P desminopathy, already depicted pre-clinical changes in myofibrillar arrangement and increased fiber bundle stiffness compatible with a pre-aged phenotype in the disease. Since the specific effect of R349P desmin on axial biomechanics in fully differentiated muscle fibers is unknown, we used our automated MyoRobot biomechatronics platform to compare passive and active biomechanics in single fibers derived from fast- and slow-twitch muscles from adult to senile mice hetero- or homozygous for this desmin mutation with wild-type littermates. Experimental protocols involved caffeine-induced Ca2+-mediated force transients, pCa-force curves, resting length-tension curves, visco-elasticity and slack-tests. We demonstrate that the presence of R349P desmin predominantly increased single fiber axial stiffness in both muscle types with a pre-aged phenotype over wild-type fibers. Axial viscosity was unaffected. Likewise, no systematic changes in Ca2+-mediated force properties were found. Notably, mutant single fibers showed faster unloaded shortening over wild-type fibers. Effects of ageing seen in the wild-type always appeared earlier in the mutant desmin fibers. Impaired R349P desmin muscle biomechanics is clearly an effect of a compromised intermediate filament network rather than secondary to fibrosis.

physiology↗

bioRxiv2019

Understanding social behaviour in mammals: Kin structure and roost fidelity in greater noctule bats

Roost fidelity is an important aspect of mammalian biology. Studying the mechanisms underlying philopatry can help us understand a species energetic requirements, ecological constraints and social organisation. Temperate bat species notably exhibit a comparatively high degree of female philopatry, resulting in maternity colonies segregated at the mitochondrial level. We focus on the greater noctule, Nyctalus lasiopterus, to study this behaviour in more depth. We make use of microsatellite data for 11 markers across 84 individuals residing in Maria Luisa Park in Seville, Spain. At the time of sampling, this urban park boasted the highest number of registered bats of this species, among which three social groups were observed to segregate spatially. We studied the distribution of pairs of individuals across filial relationship categories and relatedness estimates relative to the social group of each individual. This analysis was complemented by information on roost-use frequency among a subset of genotyped bats. We found no significant relationship between roost use and genetic distance, but there was evidence of higher group-sharing with increased levels of relatedness. Mother-daughter pairs shared the same group more often than expected, as did pairs of individuals of relatedness above 0.36. We discuss the implications of these results in terms of the behavioural ecology of temperate bats and for conservation efforts aimed at preserving them.

ecology↗

bioRxiv2019

BigTop: A Three-Dimensional Virtual Reality Tool for GWAS Visualization

BackgroundGenome-wide association studies (GWAS) are typically visualized using a two-dimensional Manhattan plot, displaying chromosomal location of SNPs along the x-axis and the negative log-10 of their p-value on the y-axis. This traditional plot provides a broad overview of the results, but offers little opportunity for interaction or expansion of specific regions, and is unable to show additional dimensions of the dataset.\n\nResultsWe created BigTop, a visualization framework in virtual reality (VR), designed to render a Manhattan plot in three dimensions, wrapping the graph around the user in a simulated cylindrical room. BigTop uses the z-axis to display minor allele frequency of each SNP, allowing for the identification of allelic variants of genes. BigTop also offers additional interactivity, allowing users to select any individual SNP and receive expanded information, including SNP name, exact values, and gene location, if applicable. BigTop is built in JavaScript using the React and A-Frame frameworks, and can be rendered using commercially available VR headsets or in a two-dimensional web browser such as Google Chrome. Data is read into BigTop in JSON format, and can be provided as either JSON or a tab-separated text file.\n\nConclusionsUsing additional dimensions and interactivity options offered through VR, we provide a new, interactive, three-dimensional representation of the traditional Manhattan plot for displaying and exploring GWAS data.

bioinformatics↗

bioRxiv2019

Direct monitoring of cAMP at the cardiac ryanodine receptor using a novel targeted fluorescence biosensor mouse

RationaleCyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger which, upon {beta}-adrenergic receptor ({beta}-AR) stimulation, acts in microdomains to regulate cardiac excitation-contraction coupling by activating the cAMP-dependent protein kinase (PKA) phosphorylation of calcium handling proteins. One crucial microdomain is in vicinity of the cardiac ryanodine receptor type 2 (RyR2) which is associated with arrhythmogenic diastolic calcium leak from the sarcoplasmic reticulum (SR) often occurring upon RyR2 hyperphosphorylation by PKA and calcium/calmodulin-dependent kinase.\n\nObjectiveWe sought to establish a real time approach capable of directly visualizing cAMP and its pathological changes in the vicinity of RyR2 by generating a proper targeted biosensor and transgenic mouse model to express it in adult cardiomyocytes.\n\nMethods and ResultsWe generated transgenic mice expressing a novel targeted fluorescent biosensor for RyR2-associated cAMP in adult mouse cardiomyocytes. In healthy cardiomyocytes, {beta}1-AR but not {beta}2-AR stimulation strongly increased local RyR2-associated cAMP levels. However, in cardiac hypertrophy induced by aortic banding, there was a marked subcellular redistribution of phosphodiesterases (PDEs) 2, 3 and 4, which included a dramatic loss of the local pool of PDE4. This was also accompanied by measurable {beta}2-AR-induced cAMP signals, increased SR calcium leak and arrhythmia susceptibility.\n\nConclusionsOur new targeted biosensor expressed in transgenic mice can visualize cAMP levels in the vicinity of cardiac RyR2 in healthy and diseased cardiomyocytes. In the future, this novel biosensor can be used to better understand alterations of RyR2-associated cAMP in cardiovascular diseases and local actions of new therapies.

cell biology↗

bioRxiv2019

Renewal theory provides a universal quantitative framework to characterise the continuous regeneration of rotational events in cardiac fibrillation

BackgroundCardiac fibrillation is thought to be maintained by rotational activity, with pivoting regions called phase singularities (PSs). Despite a century of research, no clear quantitative framework exists to model the fundamental processes responsible for the continuous formation and destruction of rotors in fibrillation.\n\nObjectiveWe conducted a multi-modality, multi-species study of AF/VF under the hypothesis that PS formation/destruction in fibrillation can be modelled as self-regenerating renewal processes, producing exponential distributions of inter-event times governed by constant rate-parameters defined by the prevailing properties of the system.\n\nMethodsPS formation/destruction was studied and cross-validated in 5 models, using basket recordings and optical mapping from: i) human persistent AF (n = 20), ii) tachypaced sheep AF (n = 5), iii) rat AF (n = 4), iv) rat VF (n = 11) and v) computer simulated AF (SIM). Hilbert phase maps were constructed. PS lifetime data were fitted by exponential probability distribution functions (PDFs) computed using maximum entropy theory, and the rate parameter ({lambda}) determined. A systematic review was conducted to cross-validate with source data from literature.\n\nResultsPS destruction/formation distributions showed good fits to an exponential in all systems (R2 [≥] 0.90). In humans,{lambda} = 4.6%/ms (95%CI,4.3,4.9)), sheep 4.4%/ms (95%CI,4.1,4.7)), rat AF 38%/ms (95%CI,22,55), rat VF 46%/ms (95%CI,31.2,60.2) and SIM 5.4%/ms (95%CI,4.1,6.7). All PS distributions identified through systematic review were exponential with {lambda} comparable to experimental data.\n\nConclusionThese results provide a universal quantitative framework to explain rotor formation and destruction in AF/VF, and a platform for therapeutic advances in cardiac fibrillation.

physiology↗

bioRxiv2019

A DNA barcode reference library of the French Polynesian shore fishes

The emergence of DNA barcoding and metabarcoding opened new ways to study biological diversity, however, the completion of DNA barcode libraries is fundamental for such approaches to succeed. This dataset is a DNA barcode reference library (fragment of Cytochrome Oxydase I gene) for 2,190 specimens representing at least 540 species of shore fishes collected over 10 years at 154 sites across the four volcanic archipelagos of French Polynesia; the Austral, Gambier, Marquesas and Society Islands, a 5,000,000 km2 area. At present, 65% of the known shore fish species of these archipelagoes possess a DNA barcode associated with preserved, photographed, tissue sampled and cataloged specimens, and extensive collection locality data. This dataset represents one of the most comprehensive DNA barcoding efforts for a vertebrate fauna to date. Considering the challenges associated with the conservation of coral reef fishes and the difficulties of accurately identifying species using morphological characters, this publicly available library is expected to be helpful for both authorities and academics in various fields.

zoology↗

bioRxiv2019

Looking for a reference for large datasets: relative reliability of visual and automatic sleep scoring

Study ObjectivesNew challenges in sleep science require to describe fine grain phenomena or to deal with large datasets. Beside the human resource challenge of scoring huge datasets, the inter- and intra-expert variability may also reduce the sensitivity of such studies. Searching for a way to disentangle the variability induced by the scoring method from the actual variability in the data, visual and automatic sleep scorings of healthy individuals were examined.\n\nMethodsA first dataset (DS1, 4 recordings) scored by 6 experts plus an autoscoring algorithm was used to characterize inter-scoring variability. A second dataset (DS2, 88 recordings) scored a few weeks later was used to investigate intra-expert variability. Percentage agreements and Congers kappa were derived from epoch-by-epoch comparisons on pairwise, consensus and majority scorings.\n\nResultsOn DS1 the number of epochs of agreement decreased when the number of expert increased, in both majority and consensus scoring, where agreement ranged from 86% (pairwise) to 69% (all experts). Adding autoscoring to visual scorings changed the kappa value from 0.81 to 0.79. Agreement between expert consensus and autoscoring was 93%. On DS2 intra-expert variability was evidenced by the kappa systematic decrease between autoscoring and each single expert between datasets (0.75 to 0.70).\n\nConclusionsVisual scoring induces inter- and intra-expert variability, which is difficult to address especially in big data studies. When proven to be reliable and if perfectly reproducible, autoscoring methods can cope with intra-scorer variability making them a sensible option when dealing with large datasets.\n\nStatement of SignificanceWe confirmed and extended previous findings highlighting the intra- and inter-expert variability in visual sleep scoring. On large datasets those variability issues cannot be completely addressed by neither practical nor statistical solutions such as group training, majority or consensus scoring.\n\nWhen an automated scoring method can be proven to be as reasonably imperfect as visual scoring but perfectly reproducible, it can serve as a reliable scoring reference for sleep studies.

neuroscience↗

bioRxiv2018

Remote control of alternative splicing in roots through TOR kinase

For plants, light is the source of energy and the most relevant regulator of growth and adaptations to the environment by inducing changes in gene expression at various levels, including alternative splicing. Chloroplasts trigger retrograde signals that control alternative splicing in leaves and roots in response to light. Here we provide evidence suggesting that sugars, derived from photosynthesis, act as mobile signals controlling alternative splicing in roots. The inhibition of TOR kinase activity diminishes the alternative splicing response to light and/or sugars in roots, showing the relevance of the TOR pathway in this signaling mechanism. Furthermore, disrupting the function of the mitochondria abolishes alternative splicing changes supporting a key role for these organelles in this signaling axis. We conclude that sugars can act as mobile signals coordinating alternative splicing responses to light throughout the whole plant, exerting this function in roots by activating the TOR pathway.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC=\"FIGDIR/small/472126v2_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (76K):\norg.highwire.dtl.DTLVardef@a8c978org.highwire.dtl.DTLVardef@1430da0org.highwire.dtl.DTLVardef@1339990org.highwire.dtl.DTLVardef@a6dd5a_HPS_FORMAT_FIGEXP M_FIG C_FIG Art by Dr. Luciana Giono.

molecular biology↗