bluuebunny/crossref_metadata_2025 huggingface dataset:
MR-Clust: Clustering of genetic variants in Mendelian randomization with similar causal estimates
Authors: Foley Christopher N , Kirk Paul D W , Burgess Stephen
Published: December 2019

Motivation

Mendelian randomization is an epidemiological technique that uses genetic variants as instrumental variables to estimate the causal effect of a risk factor on an outcome. We consider a scenario in which causal estimates based on each variant in turn differ more strongly than expected by chance alone, but the variants can be divided into distinct clusters, such that all variants in the cluster have similar causal estimates. This scenario is likely to occur when there are several distinct causal mechanisms by which a risk factor influences an outcome with different magnitudes of causal effect. We have developed an algorithm MR-Clust that finds such clusters of variants, and so can identify variants that reflect distinct causal mechanisms. Two features of our clustering algorithm are that it accounts for uncertainty in the causal estimates, and it includes ‘null’ and ‘junk’ clusters, to provide protection against the detection of spurious clusters.

Results

Our algorithm correctly detected the number of clusters in a simulation analysis, outperforming the popular Mclust method. In an applied example considering the effect of blood pressure on coronary artery disease risk, the method detected four clusters of genetic variants. A hypothesis-free search suggested that variants in the cluster with a negative effect of blood pressure on coronary artery disease risk were more strongly related to trunk fat percentage and other adiposity measures than variants not in this cluster.

Availability and Implementation

MR-Clust can be downloaded fromhttps://github.com/cnfoley/mrclust.

Contact

sb452@medschl.cam.ac.ukorchristopher.foley@mrc-bsu.cam.ac.uk

Supplementary Information

Supplementary Material is included in the submission.
Exaggerated Cortical Representation of Speech in Older Listeners: Mutual Information Analysis
Authors: Zan Peng , Presacco Alessandro , Anderson Samira , Simon Jonathan Z.
Published: December 2019

Aging is associated with an exaggerated representation of the speech envelope in auditory cortex. The relationship between this age-related exaggerated response and a listener’s ability to understand speech in noise remains an open question. Here, information-theory-based analysis methods are applied to magnetoencephalography (MEG) recordings of human listeners, investigating their cortical responses to continuous speech, using the novel non-linear measure of phase-locked mutual information between the speech stimuli and cortical responses. The cortex of older listeners shows an exaggerated level of mutual information, compared to younger listeners, for both attended and unattended speakers. The mutual information peaks for several distinct latencies: early (∼50 ms), middle (∼100 ms) and late (∼200 ms). For the late component, the neural enhancement of attended over unattended speech is affected by stimulus SNR, but the direction of this dependency is reversed by aging. Critically, in older listeners and for the same late component, greater cortical exaggeration is correlated with decreased behavioral inhibitory control. This negative correlation also carries over to speech intelligibility in noise, where greater cortical exaggeration in older listeners is correlated with worse speech intelligibility scores. Finally, an age-related lateralization difference is also seen for the ∼100 ms latency peaks, where older listeners show a bilateral response compared to younger listeners’ right-lateralization. Thus, this information-theory-based analysis provides new, and less coarse-grained, results regarding age-related change in auditory cortical speech processing, and its correlation with cognitive measures, compared to related linear measures.

New & Noteworthy

Cortical representations of natural speech are investigated using a novel non-linear approach based on mutual information. Cortical responses, phase-locked to the speech envelope, show an exaggerated level of mutual information associated with aging, appearing at several distinct latencies (∼50, ∼100 and ∼200 ms). Critically, for older listeners only, the ∼200 ms latency response components are correlated with specific behavioral measures, including behavioral inhibition and speech comprehension.
Acute stress enhances associative learning via dopamine signaling in the ventral lateral striatum
Authors: Stelly Claire E. , Tritley Sean C. , Rafati Yousef , Wanat Matthew J.
Published: December 2019

Acute stress transiently increases vigilance, whereby enhancing the detection of salient stimuli. This increased perceptual sensitivity is thought to promote associating rewarding outcomes with relevant cues. The mesolimbic dopamine system is critical for learning cue-reward associations. Dopamine levels in the ventral striatum are elevated following exposure to stress. Together, this suggests the mesolimbic dopamine system could mediate the influence of acute stress on cue-reward learning. To address this possibility, we examined how a single stressful experience influenced learning in an appetitive Pavlovian conditioning task. Male rats underwent an episode of restraint prior to the first conditioning session. This acute stress treatment augmented conditioned responding in subsequent sessions. Voltammetry recordings of mesolimbic dopamine levels demonstrated that acute stress selectively increased reward-evoked dopamine release in the ventral lateral striatum (VLS), but not in the ventral medial striatum (VMS). Antagonizing dopamine receptors in the VLS blocked the stress-induced enhancement of conditioned responding. Collectively, these findings illustrate that stress engages dopamine signaling in the VLS to facilitate appetitive learning.
Towards an evolutionarily appropriate null model: jointly inferring demography and purifying selection
Authors: Johri Parul , Charlesworth Brian , Jensen Jeffrey D.
Published: December 2019

The question of the relative evolutionary roles of adaptive and non-adaptive processes has been a central debate in population genetics for nearly a century. While advances have been made in the theoretical development of the underlying models, and statistical methods for estimating their parameters from large-scale genomic data, a framework for an appropriate null model remains elusive. A model incorporating evolutionary processes known to be in constant operation - genetic drift (as modulated by the demographic history of the population) and purifying selection – is lacking. Without such a null model, the role of adaptive processes in shaping within- and between-population variation may not be accurately assessed. Here, we investigate how population size changes and the strength of purifying selection affect patterns of variation at neutral sites near functional genomic components. We propose a novel statistical framework for jointly inferring the contribution of the relevant selective and demographic parameters. By means of extensive performance analyses, we quantify the utility of the approach, identify the most important statistics for parameter estimation, and compare the results with existing methods. Finally, we re-analyze genome-wide population-level data from a Zambian population ofDrosophila melanogaster, and find that it has experienced a much slower rate of population growth than was inferred when the effects of purifying selection were neglected. Our approach represents an appropriate null model, against which the effects of positive selection can be assessed.
Liquid-liquid microphase separation leads to formation of membraneless organelles
Authors: Ranganathan Srivastav , Shakhnovich Eugene
Published: December 2019

Proteins and nucleic acids can spontaneously self-assemble into membraneless droplet-like compartments, both in vitro and in vivo. A key component of these droplets are multi-valent proteins that possess several adhesive domains with specific interaction partners (whose number determines total valency of the protein) separated by disordered regions. Here, using multi-scale simulations we show that such proteins self-organize into micro-phase separated droplets of various sizes as opposed to the Flory-like macro-phase separated equilibrium state of homopolymers or equilibrium physical gels. We show that the micro-phase separated state is a dynamic outcome of the interplay between two competing processes: a diffusion-limited encounter between proteins, and the dynamics within small clusters that results in exhaustion of available valencies whereby all specifically interacting domains find their interacting partners within smaller clusters, leading to arrested phase separation. We first model these multi-valent chains as bead-spring polymers with multiple adhesive domains separated by semi-flexible linkers and use Langevin Dynamics (LD) to assess how key timescales depend on the molecular properties of associating polymers. Using the time-scales from LD simulations, we develop a coarse-grained kinetic model to study this phenomenon at longer times. Consistent with LD simulations, the macro-phase separated state was only observed at high concentrations and large interaction valencies. Further, in the regime where cluster sizes approach macro-phase separation, the condensed phase becomes dynamically solid-like, suggesting that it might no longer be biologically functional. Therefore, the micro-phase separated state could be a hallmark of functional droplets formed by proteins with the sticker-spacer architecture.

Significance statement

Membraneless organells (MO) are ubiquitous in ‘healthy’ living cells, with an altered state in disease. Their formation is likened to liquid-liquid phase separation (LLPS) between MO-forming proteins. However most models of LLPS predict complete macrophase separation while in reality MO’s are small droplets of various sizes, which are malleable to rapid morphological changes. Here we present a microscopic multiscale theoretical study of thermodynamics and kinetics of formation of MO. We show that MO’s are long-living dynamic structures formed as a result of arrested macrophase separation. Our study provides a direct link beween the molecular properies of MO-forming proteins and the morphology and dynamics of MO paving a path to rational design and control of MO.
Water lily (Nymphaea thermarum) draft genome reveals variable genomic signatures of ancient vascular cambium losses
Authors: Povilus Rebecca A. , DaCosta Jeffery M. , Grassa Christopher , Satyaki Prasad R. V. , Moeglein Morgan , Jaenisch Johan , Xi Zhenxiang , Mathews Sarah , Gehring Mary , Davis Charles C. , Friedman William E.
Published: December 2019

For more than 225 million years, all seed plants were woody trees, shrubs, or vines (1–4). Shortly after the origin of angiosperms ~135 million years ago (MYA) (5), the Nymphaeales (water lilies) became one of the first lineages to deviate from their ancestral, woody habit by losing the vascular cambium (6), the meristematic population of cells that produces secondary xylem (wood) and phloem. Many of the genes and gene families that regulate differentiation of secondary tissues also regulate the differentiation of primary xylem and phloem (7–9), which are produced by apical meristems and retained in nearly all seed plants. Here we sequence and assemble a draft genome of the water lily Nymphaea thermarum, an emerging system for the study of early flowering plant evolution, and compare it to genomes from other cambium-bearing and cambium-less lineages (like monocots and Nelumbo). This reveals lineage-specific patterns of gene loss and divergence. Nymphaea is characterized by a significant contraction of the HD-ZIP III transcription factors, specifically loss of REVOLUTA, which influences cambial activity in other angiosperms. We also find the Nymphaea and monocot copies of cambium-associated CLE signaling peptides display unique substitutions at otherwise highly conserved amino acids. Nelumbo displays no obvious divergence in cambium-associated genes. The divergent genomic signatures of convergent vascular cambium loss reveals that even pleiotropic genes can exhibit unique divergence patterns in association with independent trait loss events. Our results shed light on the evolution of herbaceousness – one of the key biological innovations associated with the earliest phases of angiosperm evolution.

Significance Statement

For ~225 million years, all seed plants were woody trees, shrubs, or vines. Shortly after the origin of flowering plants ~135 million years ago, Nymphaeales (water lilies) became one of the first seed plant lineages to become herbaceous through loss of the meristematic cell population known as the vascular cambium. We sequence and assemble the draft genome of the water lily Nymphaea thermarum, and compare it to genomes of other plants that have retained or lost the vascular cambium. By using both genome-wide and candidate-gene analysis, we find lineage-specific patterns of gene loss and divergence associated with cambium loss. Our reveal divergent genomic signatures of convergent trait loss in a system characterized by complex gene-trait relationships.
The human telomeric nucleosome displays distinct structural and dynamic properties
Authors: Soman Aghil , Liew Chong Wai , Teo Hsiang Ling , Berezhnoy Nikolay V. , Olieric Vincent , Korolev Nikolay , Rhodes Daniela , Nordenskiöld Lars
Published: December 2019

Telomeres protect the ends of our chromosomes and are key to maintaining genomic integrity during cell division and differentiation. However, our knowledge of telomeric chromatin and nucleosome structure at the molecular level is limited. Here, we aimed to define the structure, dynamics as well as properties in solution of the human telomeric nucleosome. We first determined the 2.2 Å crystal structure of a human telomeric nucleosome core particle (NCP) containing 145 bp DNA, which revealed the same helical path for the DNA as well as symmetric stretching in both halves of the NCP as that of the 145 bp ‘601’ NCP. In solution, the telomeric nucleosome exhibited a less stable and a markedly more dynamic structure compared to NCPs containing DNA positioning sequences. These observations provide molecular insights into how telomeric DNA forms nucleosomes and chromatin and advance our understanding of the unique biological role of telomeres.
Predicting genotypic values associated with gene interactions using neural networks: A simulation study for investigating factors affecting prediction accuracy
Authors: Onogi Akio
Published: December 2019

Genomic prediction has been applied to various species of plants and livestock to enhance breeding efficacy. Neural networks including deep neural networks are attractive candidates to predict phenotypic values. However, the properties of neural networks in predicting non-additive effects have not been clarified. In this simulation study, factors affecting the prediction of genetic values associated with gene interactions (i.e., epistasis) were investigated using multilayer perceptron. The results suggested that (1) redundant markers should be pruned, although markers in LD with QTLs are less harmful, (2) predicting epistatic genetic values with neural networks in real populations would be infeasible using training populations of 1000 samples, (3) neural networks with two or fewer hidden layers and a sufficient number of units per hidden layer would be useful, particularly when a certain number of interactions is involved, and (4) neural networks have greater capability to predict epistatic genetic values than random forests, although neural networks are more sensitive to training population size and the level of epistatic genetic variance. These lessons also would be applicable to other regression problems in which interactions between explanatory variables are expected,e.g., gene-by-environment interactions.
Two tandem mechanisms control bimodal expression of the flagellar genes inSalmonella enterica
Authors: Wang Xiaoyi , Koirala Santosh , Aldridge Phillip D. , Rao Christopher V.
Published: December 2019

Flagellar gene expression is bimodal inSalmonella enterica. Under certain growth conditions, some cells express the flagellar genes whereas others do not. This results in mixed populations of motile and non-motile cells. In the present study, we found that two independent mechanisms control bimodal expression of the flagellar genes. One was previously found to result from a double negative-feedback loop involving the flagellar regulators YdiV and FliZ. This feedback loop governs bimodal expression of class 2 genes. In this work, a second mechanism was found to govern bimodal expression of class 3 genes. In particular, class 3 gene expression is still bimodal even when class 2 gene expression is not. Using a combination of experimental and modeling approaches, we found that class 3 bimodalilty results from the σ28-FlgM developmental checkpoint.

IMPORTANCE

Many bacterial use flagella to swim in liquids and swarm over surface. InSalmonella enterica, over fifty genes are required to assemble flagella. The expression of these genes is tightly regulated. Previous studies have found that flagella gene expression is bimodal inS. enterica, which means that only a fraction of cells express flagellar genes and are motile. In the present study, we found that two separate mechanisms induce this bimodal response. One mechanism, which was previously identified, tunes the fraction of motile cells in response to nutrients. The other results from a developmental checkpoint that couples flagellar gene expression to flagellar assembly. Collectively, these results further our understanding of how flagellar gene expression is regulated inS. enterica.
Making the best of a bad job? Chick mortality and flexible female brood care in Snowy Plovers
Authors: Kupán Krisztina , Székely Tamás , Cruz-López Medardo , Seymour Keeley , Küpper Clemens
Published: December 2019

Offspring desertion represents a trade-off between current and future reproductive success. Its timing is crucial as the termination of parental care has profound consequences for the fitness of the parents and their offspring. However, the decision process involved with termination of care is still poorly understood. Snowy PloversCharadrius nivosusshow highly flexible brood care with females either deserting the brood early or providing care for an extended period. Deserting females often quickly remate and start a new breeding attempt. Using a dynamic modelling framework, we investigated the decision-making process for continuation or termination of care by females over a seven-year period. The length of female care increased over the season likely reflecting lower re-mating opportunities for deserting females late in the season. Present brood size, assessed daily during the brood care period, was strongly related to the length of female care: females were more likely to stay and care for larger than for smaller broods. Chick death and desertion frequently coincided, suggesting that poor offspring condition served as a trigger for female desertion. Overall, deserting females had a similar number of fledglings to caring females. This suggests that for many females, desertion was not a strategy to escape the shackles of monogamy and secure higher reproductive success through sequential polygamy. Rather, most deserting females made the best of a bad job when conditions were poor and their continued presence did not make a difference for the survival of their young. We conclude that when making the decision to continue or terminate care, Snowy Plover females monitor the condition of their offspring closely and adjust their care flexibly to the value and needs of their young.
HIV-1 Env induces pexophagy and an oxidative stress leading to uninfected CD4+ T cell death
Authors: Daussy Coralie F , Galais Mathilde , Pradel Baptiste , Robert-Hebmann Véronique , Sagnier Sophie , Pattingre Sophie , Biard-Piechaczyk Martine , Espert Lucile
Published: December 2019

The immunodeficiency observed in HIV-1-infected patients is mainly due to uninfected bystander CD4+ T lymphocytes death. The viral envelope glycoproteins (Env), expressed at the surface of infected cells, play a key role in this process. Env triggers autophagy, process necessary to subsequent apoptosis, and to production of Reactive Oxygen Species (ROS) in bystander CD4+ T cells. Here, we demonstrate that Env-induced oxidative stress is responsible for their death by apoptosis. Moreover, we report that peroxisomes, organelles involved in the control of oxidative stress, are targeted by Env-mediated autophagy. Indeed, we observe a selective autophagy-dependent decrease in the expression of peroxisomal proteins, catalase and PEX14, upon Env exposure, since the down-regulation of either BECLIN 1 or p62/SQSTM1 restores their expression levels. Fluorescence studies allowed us to conclude that Env-mediated autophagy degrades these entire organelles and specifically the mature ones. Together, our results on Env-induced pexophagy provide new clues on HIV-1-induced immunodeficiency.
Enhanced sensory coding in mouse vibrissal and visual cortex through TRPA1
Authors: Kheradpezhouh Ehsan , Tang Matthew F. , Mattingley Jason B. , Arabzadeh Ehsan
Published: December 2019

Transient Receptor Potential Ankyrin 1 (TRPA1) is a non-selective cation channel, which is broadly expressed throughout the body. Despite its expression in the mammalian cortex, little is known about the contribution of TRPA1 to cortical function. Here we investigate the role of TRPA1 in sensory information processing by performing electrophysiological recording and 2-photon calcium imaging from two sensory areas in mice: the primary vibrissal somatosensory cortex (vS1) and the primary visual cortex (V1). In vS1, local activation of TRPA1 by its agonist AITC significantly increased the spontaneous activity of cortical neurons, their evoked response to vibrissal stimulation, and their response range, consistent with a positive gain modulation. TRPA1 inhibition with HC-030031 reversed these modulations to below initial control gains. The gain modulations were absent in TRPA1 Knockout mice. In V1, TRPA1 activation increased the gain of direction and orientation selectivity similarly to the gain modulations observed in vS1 cortex. Linear decoding analysis of V1 population activity confirmed faster and more reliable encoding of visual signals in the presence of TRPA1 activation. Overall, our findings reveal a physiological role for TRPA1 in enhancing sensory signals in the mammalian cortex.
Cell cycle dynamics of lamina associated DNA
Authors: van Schaik Tom , Vos Mabel , Peric-Hupkes Daan , van Steensel Bas
Published: December 2019

In mammalian interphase nuclei more than one thousand large genomic regions are positioned at the nuclear lamina (NL). These lamina associated domains (LADs) are involved in gene regulation and may provide a backbone for the overall folding of interphase chromosomes. While LADs have been characterized in great detail, little is known about their dynamics during interphase, in particular at the onset of G1 phase and during DNA replication. To study these dynamics, we developed an antibody-based variant of the DamID technology (named pA-DamID) that allows us to map and visualize genome – NL interactions with high temporal resolution. Application of pA-DamID combined with synchronization and cell sorting experiments reveals that LAD – NL contacts are generally rapidly established early in G1 phase. However, LADs on the distal ∼25 Mb of most chromosomes tend to contact the NL first and then gradually detach, while centromere-proximal LADs accumulate gradually at the NL. Furthermore, our data indicate that S-phase chromatin shows transiently increased lamin interactions. These findings highlight a dynamic choreography of LAD – NL contacts during interphase progression, and illustrate the usefulness of pA-DamID to study the dynamics of genome compartmentalization.
Repeatability analysis improves the reliability of behavioral data
Authors: Rudeck Juliane , Vogl Silvia , Banneke Stefanie , Schönfelder Gilbert , Lewejohann Lars
Published: December 2019

Reliability of data has become a major concern in the course of the reproducibility crisis. Especially when studying animal behavior, confounding factors such as novel test apparatus can lead to a wide variability of data. At worst, effects of novelty or stress related behavior can mask treatment effects and the behavioral data may be misinterpreted. Habituation to the test situation is a common practice to circumvent novelty induced increases in variance and to improve the reliability of the respective measurements. However, there is a lack of published empirical knowledge regarding reasonable habituation procedures and a method validation seems to be overdue.

This study aimed at setting up a simple strategy to increase reliability of behavioral data. Therefore, exemplary data from mice tested in an Open Field (OF) arena were used to elucidate the potential of habituation and how reliability of measures can be confirmed by means of a repeatability analysis using the software R. On seven consecutive days, male C57BL/6J, BALB/cJ and 129S1/SvImJ mice were tested in an OF arena once daily and individual mouse behavior (distance travelled, average activity) was recorded. A repeatability analysis was conducted in order to estimate the reliability of measured animal behavior with regard to repeated trials of habituation.

Our data analysis revealed that monitoring animal behavior during habituation is important to determine when individual differences of the measurements are stable. Here, the mixed effect model framework proved to be a powerful tool for estimating repeatability values. Repeatability values from distance travelled and average activity increased over the habituation period, revealing that around 60 % of the variance of the data can be explained by individual differences between mice. The first day of habituation was statistically significantly different from the following 6 days in terms of distance travelled and average activity. A habituation period of three days appeared to be sufficient in this study. Overall these results emphasize the importance of habituation and in depth analysis of habituation data to define the correct starting point of the experiment for improving the reliability and reproducibility of experimental data.
Dancing bees evaluate agricultural forage resources as inferior to central urban land
Authors: Samuelson Ash E. , Schürch Roger , Leadbeater Ellouise
Published: December 2019

Recent evidence suggests that flower-rich areas within cities could play an important role in pollinator conservation, but direct comparison of agricultural and urban areas has proved challenging to perform over large scales. Here we use the waggle dances of honeybees (Apis melliferaL.) to evaluate floral resource availability over the entire season at deeply urban or agricultural sites. Through analysis of 3378 dances that were performed over two years by 20 colonies in SE England, we show that foraging trip distance is consistently lower at urban sites across the entire season, implying a higher availability of forage in heavily urbanized areas. Urban bees also collected nectar with a higher mean sugar content. From the self-reported perspective of a generalist pollinator, the modern agricultural landscapes that we studied provided insufficient and transient resources relative to heavily urbanised areas, which may represent important refuges within an impoverished landscape.
The effects of a 6-week core exercises on swimming performance of national level swimmers
Authors: Karpiński Jakub , Rejdych Wojciech , Brzozowska Dominika , Gołaś Artur , Sadowski Wojciech , Swinarew Andrzej , Stachura Alicja , Gupta Subir , Stanula Arkadiusz
Published: December 2019

The aim of this study was to assess the impact of a 6-week specialized training program aimed at strengthening core muscles to improve the effectiveness of selected elements of a swimming race in group of elite polish swimmers. Sixteen male national and international level swimmers (21.6 ± 2.2 years) participated in the research. The competitors were randomly assigned to 1 of 2 groups before the data collection process: an experimental (EG, n = 8) and control (CG, n = 8) group. Both groups of swimmers carried out the same training program in the water environment (volume and intensity), while swimmers from EG additionally carried out the specific core muscle training. The task of the swimmers was an individual swim of 50 meters freestyle, during which the kinematic parameters of start, turn and swimming techniques were recorded using the video camera system. In both groups a minor increase in the flight phase was observed during the start (EG=0.06 m, 1.8%; p=0.088; CG = 0.08 m, 2.7%; p=0.013). The time of the distance 5 m after the turn and the recorded average speed of swimming this distance in EG statistically significant improved accordingly 0.1 s (−28.6%; p<0.001) and 3.56 m·s-1(23.2%; p=0.001). In EG, a statistically significant improvement in 50-m freestyle performance was observed by 0.3 s (−1.2%, p = 0.001). The results of the research show that the implementation of isolated strength of the stabilizing muscles seems to be a valuable addition to the standard training of swimmers.
Comparison of alternative models of human movement and the spread of disease
Authors: Bjørnstad Ottar N. , Grenfell Bryan T. , Viboud Cecile , King Aaron A.
Published: December 2019

Predictive models for the spatial spread of infectious diseases has received much attention in recent years as tools for the management of infectious diseas outbreaks. Prominently, various versions of the so-called gravity model, borrowed from transportation theory, have been used. However, the original literature suggests that the model has some potential misspecifications inasmuch as it fails to capture higher-order interactions among population centers. The fields of economics, geography and network sciences holds alternative formulations for the spatial coupling within and among conurbations. These includes Stouffer’s rank model, Fotheringham’s competing destinations model and the radiation model of Simini et al. Since the spread of infectious disease reflects mobility through the filter of age-specific susceptibility and infectivity and since, moreover, disease may alter spatial behavior, it is essential to confront with epidemiological data on spread. To study their relative merit we, accordingly, fit variants of these models to the uniquely detailed dataset of prevaccination measles in the 954 cities and towns of England and Wales over the years 1944-65 and compare them using a consistent likelihood framework. We find that while the gravity model is a reasonable first approximation, both Stouffer’s rank model, an extended version of the radiation model and the Fotheringham competing destinations model provide significantly better fits, Stouffer’s model being the best. Through a new method of spatially disaggregated likelihoods we identify areas of relatively poorer fit, and show that it is indeed in densely-populated conurbations that higher order spatial interactions are most important. Our main conclusion is that it is premature to narrow in on a single class of models for predicting spatial spread of infectious disease. The supplemental materials contain all code for reproducing the results and applying the methods to other data sets.

Author summary

The ability to predict how infectious disease will spread is of great importance in the face of the numerous emergent and re-emergent pathogens that currently threatening human well-being. We identified a variety of alternative models that predict human mobility as as a function of population distribution across a landscape. These consider some models that account for pair-wise interactions between population centers, as well as some that allow for higher-order interactions. We trained the models using a uniquely rich spatiotemporal data set on pre-vaccination measles in England and wales (1944-65), which comprises more than a million records from 954 cities and towns. Likelihood rankings of the different models reveal strong evidence for higher-order interactions in the form of competition among cities as destinations for travelers and, thus, dilution of spatial transmission. The currently most commonly used so-called ‘gravity’ models were far from the best in capturing spatial disease dynamics.
Self-organization in brain tumors: how cell morphology and cell density influence glioma pattern formation
Authors: Jamous Sara , Comba Andrea , Lowenstein Pedro , Motsch Sebastien
Published: December 2019

Modeling cancer cells is essential to better understand the dynamic nature of brain tumors and glioma cells, including their invasion of normal brain. Our goal is to study how the morphology of the glioma cell influences the formation of patterns of collective behavior such as flocks (cells moving in the same direction) or streams (cells moving in opposite direction) referred to asoncostream. We have observed experimentally that the presence of oncostreams correlates with tumor progression. We propose an original agent-based model that considers each cell as an ellipsoid. We show that stretching cells from round to ellipsoid increases stream formation.

A systematic numerical investigation of the model was implemented in ℝ2. We deduce a phase diagram identifying key regimes for the dynamics (e.g. formation of flocks, streams, scattering). Moreover, we study the effect of cellular density and show that, in contrast to classical models of flocking, increasing cellular density reduces the formation of flocks. We observe similar patterns in ℝ3with the noticeable difference that stream formation is more ubiquitous compared to flock formation.

Author summary

Self-organization is the formation of large-scale multicellular patterns that result exclusively from the interactions amongst constituent single cells. To establish the existence of self-organization in brain tumors we used agent-based modeling based on data extracted from static and dynamic genetically engineered mouse glioma models. Implementation of our model in ℝ2identifies the dynamics that lead to formation of flocks (cells moving in a single direction), streams (cells moving in two directions), and cells moving as swarms or scattering. Increasing cellular density reduced formation of flocks and increased the formation of streams both in ℝ2and in ℝ3. These results demonstrate the detailed mechanism leading to self-organization in brain tumors. As increasing density of oncostreams correlates with tumor malignancy, we establish a pathophysiological link between self-organization of glioma tumors and glioma malignancy. We propose the dismantling of oncostreams as a new therapeutic approach to the treatment of brain tumors.
TRA1: a locus responsible for controllingAgrobacterium-mediated transformability in barley
Authors: Orman-Ligeza Beata , Harwood Wendy , Hedley Pete E. , Hinchcliffe Alison , Macaulay Malcolm , Uauy Cristobal , Trafford Kay
Published: December 2019

In barley (Hordeum vulgareL.),Agrobacterium-mediated transformation efficiency is highly dependent on genotype with very few cultivars being amenable to transformation. Golden Promise is the cultivar most widely used for barley transformation and developing embryos are the most common donor tissue. We tested whether barley mutants with abnormally large embryos were more or less amenable to transformation and discovered that mutant M1460 had a transformation efficiencies similar to that of Golden Promise. The large-embryo phenotype of M1460 is due to mutation at theLYS3locus. There are three other barley lines with independent mutations at the sameLYS3locus, and one of these, Risø1508 has an identical missense mutation to that in M1460. However, none of thelys3mutants except M1460 were transformable showing that the locus responsible for transformation efficiency,TRA1, was notLYS3but another locus unique to M1460. To identifyTRA1, we generated a mapping population by crossing M1460 to the cultivar Optic, which is recalcitrant to transformation. After four rounds of backcrossing to Optic, plants were genotyped and their progeny were tested for transformability. Some of the progeny lines were transformable at high efficiencies similar to those seen for the parent M1460 and some were not transformable, like Optic. A region on chromosome 2H inherited from M1460 is present in transformable lines only. We propose that one of the 225 genes in this region isTRA1.
Adding insult to injury: Effects of chronic oxybenzone exposure and elevated temperature on two reef-building corals
Authors: Wijgerde Tim , van Ballegooijen Mike , Nijland Reindert , van der Loos Luna , Kwadijk Christiaan , Osinga Ronald , Murk Albertinka , Slijkerman Diana
Published: December 2019

We studied the effect of chronic oxybenzone exposure and elevated temperature on coral health. Microcolonies ofStylophora pistillataandAcropora tenuiswere cultured in 20 flow-through aquaria, of which 10 were exposed to oxybenzone at a field-relevant concentration of ~0.06 μg L−1at 26 °C. After two weeks, half of the corals experienced a heat wave culminating at 33 °C. AllS. pistillatacolonies survived the heat wave, although heat reduced growth and zooxanthellae density, irrespective of oxybenzone.A. tenuissurvival was reduced to 0% at 32 °C, and oxybenzone accelerated mortality. Oxybenzone and heat significantly reduced photosynthetic yield in both species, causing a 5% and 22−33% decrease, respectively. In addition, combined oxybenzone and temperature stress altered the abundance of five bacterial families in the microbiome ofS. pistillata. Our results suggest that oxybenzone adds insult to injury by further weakening corals in the face of global warming.

Highlights

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Chronic effect study on corals combining oxybenzone and elevated temperature

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Oxybenzone affected photosystem II of coral photosymbionts and altered coral microbiome

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Temperature effects were stronger than oxybenzone effects

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Sensitivities were species-dependent

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Oxybenzone adds insult to injury by weakening corals in the face of global warming
Identifying the causes and consequences of assembly gaps using a multiplatform genome assembly of a bird-of-paradise
Authors: Peona Valentina , Blom Mozes P.K. , Xu Luohao , Burri Reto , Sullivan Shawn , Bunikis Ignas , Liachko Ivan , Jønsson Knud A. , Zhou Qi , Irestedt Martin , Suh Alexander
Published: December 2019

Genome assemblies are currently being produced at an impressive rate by consortia and individual laboratories. The low costs and increasing efficiency of sequencing technologies have opened up a whole new world of genomic biodiversity. Although these technologies generate high-quality genome assemblies, there are still genomic regions difficult to assemble, like repetitive elements and GC-rich regions (genomic “dark matter”). In this study, we compare the efficiency of currently used sequencing technologies (short/linked/long reads and proximity ligation maps) and combinations thereof in assembling genomic dark matter starting from the same sample. By adopting different de-novo assembly strategies, we were able to compare each individual draft assembly to a curated multiplatform one and identify the nature of the previously missing dark matter with a particular focus on transposable elements, multi-copy MHC genes, and GC-rich regions. Thanks to this multiplatform approach, we demonstrate the feasibility of producing a high-quality chromosome-level assembly for a non-model organism (paradise crow) for which only suboptimal samples are available. Our approach was able to reconstruct complex chromosomes like the repeat-rich W sex chromosome and several GC-rich microchromosomes. Telomere-to-telomere assemblies are not a reality yet for most organisms, but by leveraging technology choice it is possible to minimize genome assembly gaps for downstream analysis. We provide a roadmap to tailor sequencing projects around the completeness of both the coding and non-coding parts of the genomes.
HyPo: Super Fast & Accurate Polisher for Long Read Genome Assemblies
Authors: Kundu Ritu , Casey Joshua , Sung Wing-Kin
Published: December 2019

Efforts towards making population-scale long read genome assemblies (especially human genomes) viable have intensified recently with the emergence of many fast assemblers. The reliance of these fast assemblers on polishing for the accuracy of assemblies makes it crucial. We present HyPo–aHybridPolisher–that utilises short as well as long reads within a single run to polish a long read assembly of small and large genomes. It exploits unique genomic kmers to selectively polish segments of contigs using partial order alignment of selective read-segments. As demonstrated on human genome assemblies, Hypo generates significantly more accurate polished assemblies in about one-third time with about half the memory requirements in comparison to Racon (the widely used polisher currently).
A neurocomputational model for intrinsic reward
Authors: Chew Benjamin , Blain Bastien , Dolan Raymond J , Rutledge Robb B
Published: December 2019

Standard economic indicators provide an incomplete picture of what we value both as individuals and as a society. Furthermore, canonical macroeconomic measures, such as GDP, do not account for non-market activities (e.g., cooking, childcare) that nevertheless impact well-being. Here, we introduce a computational tool that measures the affective value of experiences (e.g., playing a musical instrument without errors). We go on to validate this tool with neural data, using fMRI to measure neural activity in male and female human subjects performing a reinforcement learning task that incorporated periodic ratings of subjective affective state. Learning performance determined level of payment (i.e., extrinsic reward). Crucially, the task also incorporated a skilled performance component (i.e., intrinsic reward) which did not influence payment. Both extrinsic and intrinsic rewards influenced affective dynamics, and their relative influence could be captured in our computational model. Individuals for whom intrinsic rewards had a greater influence on affective state than extrinsic rewards had greater ventromedial prefrontal cortex (vmPFC) activity for intrinsic than extrinsic rewards. Thus, we show that computational modelling of affective dynamics can index the subjective value of intrinsic relative to extrinsic rewards, a ‘computational hedonometer’ that reflects both behavior and neural activity that quantifies the affective value of experience.

SIGNIFICANCE STATEMENT

Traditional economic indicators are increasingly recognized to provide an incomplete picture of what we value as a society. Standard economic approaches struggle to accurately assign values to non-market activities that nevertheless may be intrinsically rewarding, prompting a need for new tools to measure what really matters to individuals. Using a combination of neuroimaging and computational modeling, we show that despite their lack of instrumental value, intrinsic rewards influence subjective affective state and ventromedial prefrontal cortex activity. The relative degree to which extrinsic and intrinsic rewards influence affective state is predictive of their relative impacts on neural activity, confirming the utility of our approach for measuring the affective value of experiences and other non-market activities in individuals.
X-ray 3D imaging of gene expression in whole-mount murine brain by microCT, implication for functional analysis of tRNA endonuclease 54 gene mutated in pontocerebellar hypoplasia
Authors: Ermakova Olga , Orsini Tiziana , Fruscoloni Paolo , Chiani Francesco , Gambadoro Alessia , Putti Sabrina , Cirilli Maurizio , Mezzi Alessio , Kaciulis Saulius , Raspa Marcello , Scavizzi Ferdinando , Tocchini-Valentini Glauco P.
Published: December 2019

Acquisition of detailed structural and molecular information from intact biological samples, while preserving cellular three-dimensional structures, still represents a challenge for biological studies aiming to unravel system functions. Here we describe a novel X-ray-based methodology for analysis of gene expression pattern in intact murine brain ex vivo by microCT. The method relays on detection of bromine molecules in the products of enzymatic reaction generated by theβ-galactosidase (lacZ) gene reporter. To demonstrate the feasibility of the method, the analysis of the expression pattern of tRNA endonuclease 54 (Tsen54)-lacZ reporter gene in the whole-mount murine brain in semi-quantitative manner is performed. Mutations in Tsen54 gene causes pontocerebellar hypoplasia (PCH), severe neurodegenerative disorder with both mental and motor deficits. Comparing relative levels of Tsen54 gene expression, we have demonstrated that highest Tsen54 expression observed in anatomical brain substructures important for the normal motor and memory functions in mice. In the forebrain strong expression in perirhinal, retrosplenial and secondary motor areas was observed. In olfactory area Tsen54 is highly expressed in the nucleus of the lateral olfactory tract, anterior olfactory and bed nuclei, while in hypothalamus in lateral mammillary nucleus and preoptic area. In hindbrain Tsen54 is expressed in the reticular, cuneate and trigeminal nuclei of medulla, and in pontine gray of pons and in cerebellum, in the molecular and Purkinje cell layers. Delineating anatomical brain regions in which Tsen54 is strongly expressed will allow functionally address the role Tsen54 gene in normal physiology and in PCH disease.

Significance Statement

Characterization of gene expression pattern in the brain of model organisms is critical for unravelling the gene function in normal physiology and disease. It is performed by optical imaging of the two-dimensional brain sections which then assembled in volume images. Here we applied microCT platform, which allows three-dimensional imaging of non transparent samples, for analysis of gene expression. This method based on detection by X-ray the bromine molecules presented in the products generated by enzymatic activity of b-galactosidase reporter gene. With this method we identify anatomical brain substructures in which Tsen54 gene, mutated in pontocerebellar hypoplasia disease, is expressed.
Modulation of Yorkie activity by alternative splicing is required for developmental stability
Authors: Srivastava Diwas , de Toledo Marion , Manchon Laurent , Tazi Jamal , Juge François
Published: December 2019

The mechanisms that contribute to developmental stability are barely known. Here we show that alternative splicing ofyorkie(yki) is required for developmental stability inDrosophila. Yki encodes the effector of the Hippo pathway that has a central role in controlling organ growth and regeneration. We identify the splicing factor B52 as necessary for inclusion ofykialternative exon 3 that encodes one of the two WW domains of Yki protein. B52 depletion favors expression of Yki1 isoform carrying a single WW domain, and reduces growth in part through modulation ofykialternative splicing. Compared to the canonical Yki2 isoform containing two WW domains, Yki1 isoform has reduced transcriptional and growth-promoting activities, decreased binding to PPxY-containing partners, and lacks the ability to bridge two proteins containing PPxY motifs. Yet, Yki1 and Yki2 interact similarly with transcription factors and can thus competein vivo. Strikingly, flies deprived from Yki1 isoform exhibit increased fluctuating wing asymmetry, a signal of increased developmental noise. Our results identifyykialternative splicing as a new level of control of the Hippo pathway and provide the first experimental evidence that alternative splicing participates in developmental robustness.