bluuebunny/crossref_metadata_2025 huggingface dataset:
A simple mathematical model of allometric exponential growth describes the early three-dimensional growth dynamics of secondary xylem in Arabidopsis roots
Authors: Thamm Anna , Sanegre-Sans Sabina , Paisley Jennifer , Meader Susana , Milhinhos Ana , Contera Sonia , Agusti Javier
Published: March 2019

Unravelling the specific growth dynamics of key tissues and organs is fundamental to understand how multicellular organisms orchestrate their different growth programmes. In plants, the secondary growth (thickening) of stems and roots provides the mechanical support that plants need to achieve their developmental potential. We used conventional anatomical and microscopy techniques, image-processing software, and quantitative analysis to understand and mathematically describe the growth dynamics of the early developmental stages of secondary xylem (the main tissue developed during secondary growth). Results show that such early developmental stages are characterized by exponential expansion of secondary xylem in three dimensions in the form of an inverted cone, with a power law that describes the relationship between the area of the base and the longitudinal progression (height) of the growing secondary xylem cone over time with a scaling exponent of 2/5: the signature of allometric growth. Our work constitutes a starting point for future modelling of secondary xylem in particular and secondary growth in general.
A diffuse interface model for the analysis of propagating bulges in cylindrical balloons
Authors: Lestringant C. , Audoly B.
Published: March 2019

With the aim to characterize the formation and propagation of bulges in cylindrical rubber balloons, we carry out an expansion of the nonlinear axisymmetric membrane model assuming slow axial variations. We obtain a diffuse interface model similar to that introduced by van der Waals in the context of liquid–vapour phase transitions. This provides a quantitative basis to the well-known analogy between propagating bulges and phase transitions. The diffuse interface model is amenable to numerical as well as analytical solutions, including linear and nonlinear bifurcation analyses. Comparisons to the original membrane model reveal that the diffuse interface model captures the bulging phenomenon very accurately, even for well-localized phase boundaries.
Edgeworth expansions for slow–fast systems with finite time-scale separation
Authors: Wouters Jeroen , Gottwald Georg A.
Published: March 2019

We derive Edgeworth expansions that describe corrections to the Gaussian limiting behaviour of slow–fast systems. The Edgeworth expansion is achieved using a semi-group formalism for the transfer operator, where a Duhamel–Dyson series is used to asymptotically determine the corrections at any desired order of the time-scale parameterε. The corrections involve integrals over higher-order auto-correlation functions. We develop a diagrammatic representation of the series to control the combinatorial wealth of the asymptotic expansion inεand provide explicit expressions for the first two orders. At a formal level, the expressions derived are valid in the case when the fast dynamics is stochastic as well as when the fast dynamics is entirely deterministic. We corroborate our analytical results with numerical simulations and show that our method provides an improvement on the classical homogenization limit which is restricted to the limit of infinite time-scale separation.
Model selection for hybrid dynamical systems via sparse regression
Authors: Mangan N. M. , Askham T. , Brunton S. L. , Kutz J. N. , Proctor J. L.
Published: March 2019

Hybrid systems are traditionally difficult to identify and analyse using classical dynamical systems theory. Moreover, recently developed model identification methodologies largely focus on identifying a single set of governing equations solely from measurement data. In this article, we develop a new methodology, Hybrid-Sparse Identification of Nonlinear Dynamics, which identifies separate nonlinear dynamical regimes, employs information theory to manage uncertainty and characterizes switching behaviour. Specifically, we use the nonlinear geometry of data collected from a complex system to construct a set of coordinates based on measurement data and augmented variables. Clustering the data in these measurement-based coordinates enables the identification of nonlinear hybrid systems. This methodology broadly empowers nonlinear system identification without constraining the data locally in time and has direct connections to hybrid systems theory. We demonstrate the success of this method on numerical examples including a mass–spring hopping model and an infectious disease model. Characterizing complex systems that switch between dynamic behaviours is integral to overcoming modern challenges such as eradication of infectious diseases, the design of efficient legged robots and the protection of cyber infrastructures.
Kazantsev dynamo in turbulent compressible flows
Authors: Martins Afonso Marco , Mitra Dhrubaditya , Vincenzi Dario
Published: March 2019

We consider the kinematic fluctuation dynamo problem in a flow that is random, white-in-time, with both solenoidal and potential components. This model is a generalization of the well-studied Kazantsev model. If both the solenoidal and potential parts have the same scaling exponent, then, as the compressibility of the flow increases, the growth rate decreases but remains positive. If the scaling exponents for the solenoidal and potential parts differ, in particular if they correspond to typical Kolmogorov and Burgers values, we again find that an increase in compressibility slows down the growth rate but does not turn it off. The slow down is, however, weaker and the critical magnetic Reynolds number is lower than when both the solenoidal and potential components display the Kolmogorov scaling. Intriguingly, we find that there exist cases, when the potential part is smoother than the solenoidal part, for which an increase in compressibility increases the growth rate. We also find that the critical value of the scaling exponent above which a dynamo is seen is unity irrespective of the compressibility. Finally, we realize that the dimension
d
 = 3 is special, as for all other values of
d
the critical exponent is higher and depends on the compressibility.
Microbial communities in hummingbird feeders are distinct from floral nectar and influenced by bird visitation
Authors: Lee Casie , Tell Lisa A. , Hilfer Tiffany , Vannette Rachel L.
Published: March 2019

Human provisioning can shape resource availability for wildlife, but consequences for microbiota availability and exchange remain relatively unexplored. Here, we characterized microbial communities on bills and faecal material of hummingbirds and their food resources, including feeders and floral nectar. We experimentally manipulated bird visitation to feeders and examined effects on sucrose solution microbial communities. Birds, feeders and flowers hosted distinct bacterial and fungal communities. Proteobacteria comprised over 80% of nectar bacteria but feeder solutions contained a high relative abundance of Proteobacteria, Firmicutes and Actinobacteria. Hummingbirds hosted bacterial taxa commonly found in other birds and novel genera including
Zymobacter
[Proteobacteria] and Ascomycete fungi. For feeders, bird-visited and unvisited solutions both accumulated abundant microbial populations that changed solution pH, but microbial composition was largely determined by visitation treatment. Our results reveal that feeders host abundant microbial populations, including some bird-associated microbial taxa. Microbial taxa in feeders were primarily non-pathogenic bacteria and fungi but differed substantially from those in floral nectar. These results demonstrate that human provisioning influences microbial intake by free-ranging hummingbirds; however, it is unknown how these changes impact hummingbird gastrointestinal flora or health.
Tree diversity increases robustness of multi-trophic interactions
Authors: Fornoff Felix , Klein Alexandra-Maria , Blüthgen Nico , Staab Michael
Published: March 2019

Multi-trophic interactions maintain critical ecosystem functions. Biodiversity is declining globally, while responses of trophic interactions to biodiversity change are largely unclear. Thus, studying responses of multi-trophic interaction robustness to biodiversity change is crucial for understanding ecosystem functioning and persistence. We investigate plant–Hemiptera (antagonism) and Hemiptera–ant (mutualism) interaction networks in response to experimental manipulation of tree diversity. We show increased diversity at both higher trophic levels (Hemiptera and ants) and increased robustness through redundancy of lower level species of multi-trophic interactions when tree diversity increased. Hemiptera and ant diversity increased with tree diversity through non-additive diversity effects. Network analyses identified that tree diversity also increased the number of tree and Hemiptera species used by Hemiptera and ant species, and decreased the specialization on lower trophic level species in both mutualistic and antagonist interactions. Our results demonstrate that bottom-up effects of tree diversity ascend through trophic levels regardless of interaction type. Thus, local tree diversity is a key driver of multi-trophic community diversity and interaction robustness in forests.
Rapid morphological evolution in placental mammals post-dates the origin of the crown group
Authors: Halliday Thomas J. D. , dos Reis Mario , Tamuri Asif U. , Ferguson-Gow Henry , Yang Ziheng , Goswami Anjali
Published: March 2019

Resolving the timing and pattern of early placental mammal evolution has been confounded by conflict among divergence date estimates from interpretation of the fossil record and from molecular-clock dating studies. Despite both fossil occurrences and molecular sequences favouring a Cretaceous origin for Placentalia, no unambiguous Cretaceous placental mammal has been discovered. Investigating the differing patterns of evolution in morphological and molecular data reveals a possible explanation for this conflict. Here, we quantified the relationship between morphological and molecular rates of evolution. We show that, independent of divergence dates, morphological rates of evolution were slow relative to molecular evolution during the initial divergence of Placentalia, but substantially increased during the origination of the extant orders. The rapid radiation of placentals into a highly morphologically disparate Cenozoic fauna is thus not associated with the origin of Placentalia, but post-dates superordinal origins. These findings predict that early members of major placental groups may not be easily distinguishable from one another or from stem eutherians on the basis of skeleto-dental morphology. This result supports a Late Cretaceous origin of crown placentals with an ordinal-level adaptive radiation in the early Paleocene, with the high relative rate permitting rapid anatomical change without requiring unreasonably fast molecular evolutionary rates. The lack of definitive Cretaceous placental mammals may be a result of morphological similarity among stem and early crown eutherians, providing an avenue for reconciling the fossil record with molecular divergence estimates for Placentalia.
A phylum-wide survey reveals multiple independent gains of head regeneration in Nemertea
Authors: Zattara Eduardo E. , Fernández-Álvarez Fernando A. , Hiebert Terra C. , Bely Alexandra E. , Norenburg Jon L.
Published: March 2019

Animals vary widely in their ability to regenerate, suggesting that regenerative ability has a rich evolutionary history. However, our understanding of this history remains limited because regenerative ability has only been evaluated in a tiny fraction of species. Available comparative regeneration studies have identified losses of regenerative ability, yet clear documentation of gains is lacking. We assessed ability to regenerate heads and tails either through our own experiments or from literature reports for 35 species of Nemertea spanning the diversity of the phylum, including representatives of 10 families and all three orders. We generated a phylogenetic framework using sequence data to reconstruct the evolutionary history of head and tail regenerative ability across the phylum and found that all evaluated species can remake a posterior end but surprisingly few could regenerate a complete head. Our analysis reconstructs a nemertean ancestor unable to regenerate a head and indicates independent gains of head regenerative ability in at least four separate lineages, with one of these gains taking place as recently as the last 10–15 Myr. Our study highlights nemerteans as a valuable group for studying evolution of regeneration and identifying mechanisms associated with repeated gains of regenerative ability.
Evolutionary design principles in metabolism
Authors: Sambamoorthy Gayathri , Sinha Himanshu , Raman Karthik
Published: March 2019

Microorganisms are ubiquitous and adapt to various dynamic environments to sustain growth. These adaptations accumulate, generating new traits forming the basis of evolution. Organisms adapt at various levels, such as gene regulation, signalling, protein–protein interactions and metabolism. Of these, metabolism forms the integral core of an organism for maintaining the growth and function of a cell. Therefore, studying adaptations in metabolic networks is crucial to understand the emergence of novel metabolic capabilities. Metabolic networks, composed of enzyme-catalysed reactions, exhibit certain repeating paradigms or
design principles
that arise out of different selection pressures. In this review, we discuss the design principles that are known to exist in metabolic networks, such as functional redundancy, modularity, flux coupling and exaptations. We elaborate on the studies that have helped gain insights highlighting the interplay of these design principles and adaptation. Further, we discuss how evolution plays a role in exploiting such paradigms to enhance the robustness of organisms. Looking forward, we predict that with the availability of ever-increasing numbers of bacterial, archaeal and eukaryotic genomic sequences, novel design principles will be identified, expanding our understanding of these paradigms shaped by varied evolutionary processes.
Moralizing gods, impartiality and religious parochialism across 15 societies
Authors: Lang Martin , Purzycki Benjamin G. , Apicella Coren L. , Atkinson Quentin D. , Bolyanatz Alexander , Cohen Emma , Handley Carla , Kundtová Klocová Eva , Lesorogol Carolyn , Mathew Sarah , McNamara Rita A. , Moya Cristina , Placek Caitlyn D. , Soler Montserrat , Vardy Thomas , Weigel Jonathan L. , Willard Aiyana K. , Xygalatas Dimitris , Norenzayan Ara , Henrich Joseph
Published: March 2019

The emergence of large-scale cooperation during the Holocene remains a central problem in the evolutionary literature. One hypothesis points to culturally evolved beliefs in punishing, interventionist gods that facilitate the extension of cooperative behaviour toward geographically distant co-religionists. Furthermore, another hypothesis points to such mechanisms being constrained to the religious ingroup, possibly at the expense of religious outgroups. To test these hypotheses, we administered two behavioural experiments and a set of interviews to a sample of 2228 participants from 15 diverse populations. These populations included foragers, pastoralists, horticulturalists, and wage labourers, practicing Buddhism, Christianity, and Hinduism, but also forms of animism and ancestor worship. Using the Random Allocation Game (RAG) and the Dictator Game (DG) in which individuals allocated money between themselves, local and geographically distant co-religionists, and religious outgroups, we found that higher ratings of gods as monitoring and punishing predicted decreased local favouritism (RAGs) and increased resource-sharing with distant co-religionists (DGs). The effects of punishing and monitoring gods on outgroup allocations revealed between-site variability, suggesting that in the absence of intergroup hostility, moralizing gods may be implicated in cooperative behaviour toward outgroups. These results provide support for the hypothesis that beliefs in monitoring and punitive gods help expand the circle of sustainable social interaction, and open questions about the treatment of religious outgroups.
Acclimatization of massive reef-building corals to consecutive heatwaves
Authors: DeCarlo Thomas M. , Harrison Hugo B. , Gajdzik Laura , Alaguarda Diego , Rodolfo-Metalpa Riccardo , D'Olivo Juan , Liu Gang , Patalwala Diana , McCulloch Malcolm T.
Published: March 2019

Reef-building corals typically live close to the upper limits of their thermal tolerance and even small increases in summer water temperatures can lead to bleaching and mortality. Projections of coral reef futures based on forecasts of ocean temperatures indicate that by the end of this century, corals will experience their current thermal thresholds annually, which would lead to the widespread devastation of coral reef ecosystems. Here, we use skeletal cores of long-lived
Porites
corals collected from 14 reefs across the northern Great Barrier Reef, the Coral Sea, and New Caledonia to evaluate changes in their sensitivity to heat stress since 1815. High-density ‘stress bands’—indicative of past bleaching—first appear during a strong pre-industrial El Niño event in 1877 but become significantly more frequent in the late twentieth and early twenty-first centuries in accordance with rising temperatures from anthropogenic global warming. However, the proportion of cores with stress bands declines following successive bleaching events in the twenty-first century despite increasing exposure to heat stress. Our findings demonstrate an increase in the thermal tolerance of reef-building corals and offer a glimmer of hope that at least some coral species can acclimatize fast enough to keep pace with global warming.
Narrow habitat breadth and late-summer emergence increases extinction vulnerability in Central European bees
Authors: Hofmann Michaela M. , Zohner Constantin M. , Renner Susanne S.
Published: March 2019

Evaluating intrinsic and extrinsic traits that predispose species to local extinction is important for targeting conservation efforts. Among the species of special concern in Europe are bees, which, along with butterflies, are the best monitored insects. Bees are most species-rich in Mediterranean-type climates with short winters, warm springs, and dry summers. In Central Europe, climate warmingper seis, therefore, expected to benefit most bee species, while pesticides and the loss of habitats and plant diversity should constitute threats. Here, we use the bee fauna of Germany, which has been monitored for Red Lists for over 40 years, to analyse the effects of habitat breadth, pollen specialization, body size, nesting sites, sociality, duration of flight activity, and time of emergence during the season. We tested each factor's predictive power against changes in commonness and Red List status, using phylogenetically informed hierarchical Bayesian (HB) models. Extinction vulnerability is strongly increased in bees flying in late summer, with a statistical model that included flight time, habitat preference, and duration of activity correctly predicting the vulnerability status of 85% of the species. Conversely, spring emergence and occurrence in urban areas each reduce vulnerability, pointing to intensive land use especially harming summer-active bees, with the combination of these factors currently shifting Germany's bee diversity towards warm-adapted, spring-flying, city-dwelling species.
Quantifying the efficiency and biases of forestSaccharomycessampling strategies
Authors: Boynton Primrose J. , Kowallik Vienna , Landermann Doreen , Stukenbrock Eva H.
Published: March 2019

Saccharomycesyeasts are emerging as model organisms for ecology and evolution, and researchers need environmentalSaccharomycesisolates to test ecological and evolutionary hypotheses. However, methods for isolatingSaccharomycesfrom nature have not been standardized and isolation methods may influence the genotypes and phenotypes of studied strains. We compared the effectiveness and potential biases of an established enrichment culturing method against a newly developed direct plating method for isolating forest floorSaccharomycesspp. In a European forest, enrichment culturing was both less successful at isolatingS. paradoxusper sample collected and less labor intensive per isolatedS. paradoxuscolony than direct isolation. The two methods sampled similarS. paradoxusdiversity: the number of unique genotypes sampled (i.e., genotypic diversity) perS. paradoxusisolate and average growth rates ofS. paradoxusisolates did not differ between the two methods, and growth rate variances (i.e., phenotypic diversity) only differed in one of three tested environments. However, enrichment culturing did detect rareS. cerevisiaein the forest habitat, and also found twoS. paradoxusisolates with outlier phenotypes. Our results validate the historically common method of using enrichment culturing to isolate representative collections of environmentalSaccharomyces.We recommend that researchers choose aSaccharomycessampling method based on resources available for sampling and isolate screening. Researchers interested in discovering newSaccharomycesphenotypes or rareSaccharomycesspecies from natural environments may also have more success using enrichment culturing. We include step-by-step sampling protocols in the supplemental materials.
Improved HLA-based prediction of coeliac disease identifies two novel HLA risk modifiers, DQ6.2 and DQ7.3
Authors: Erlichster Michael , Bedo Justin , Skafidas Efstratios , Kwan Patrick , Kowalczyk Adam , Goudey Benjamin
Published: March 2019

Purpose

Human Leukocyte Antigen (HLA) testing is useful in the clinical work-up of coeliac disease (CD), with high negative but low positive predictive value. We construct a genomic risk score (GRS) using HLA risk loci to improve CD prediction and guide exclusion criteria.

Methods

Imputed HLA genotypes for five European CD case-control GWAS (n>15,000) were used to construct and validate an HLA based risk models (HDQ15). Conditioning on this score, we identified novel HLA interactions which modified CD risk, and integrated these novel alleles into a new risk score (HDQ17).

Results

A GRS from HLA risk allele genotypes yields performance equivalent to a state-of-the-art GRS (GRS228) using 228 single nucleotide polymorphisms (SNPs) and significantly improves upon all previous HLA based risk models. Conditioning on this model, we find two novel associations, HLA-DQ6.2 and HLA-DQ7.3, that interact significantly with HLA-DQ2.5 (p = 2.51 × 10−9, 1.99 × 10−7 for DQ6.2 and DQ7.3 respectively). These epistatic interactions yield the best performing risk score (HDQ17) which retains performance when implemented using 6 tag SNPs. Using the HDQ17 model, the positive predictive value of CD testing in high risk populations increases from 17.5% to 27.1% while maintaining a negative predictive value above 99%.

Conclusion

Our proposed HLA-based GRS achieves state-of-the-art risk prediction, helps elucidate further risk factors and improves HLA typing exclusionary criteria, which may reduce the number of patients requiring unnecessary endoscopies.
CA1 pyramidal cells organize an episode by segmented and ordered events
Authors: Sun Chen , Yang Wannan , Martin Jared , Tonegawa Susumu
Published: March 2019

A prevailing view is that the brain represents episodic experience as the continuous moment to moment changes in the experience. Whether the brain also represents the same experience as a sequence of discretely segmented events, is unknown. Here, we report a hippocampal CA1 “chunking code”, tracking an episode as its discrete event subdivisions (“chunks”) and the sequential relationships between them. The chunking code is unaffected by unpredicted variations within the events, reflecting the code’s flexible nature by being organized around events as abstract units. The chunking code changes accordingly when relationships between events are disrupted or modified. The discrete chunking code and continuous spatial code are represented in the same cells, but in an orthogonal manner, and can be independently perturbed. Optogenetic inactivation of MEC inputs to CA1 disrupts the chunking but not spatial code. The chunking code may be fundamental for representing an episode, alongside codes tracking continuous changes.
Genetic drift in range expansions is very sensitive to density feedback in dispersal and growth
Authors: Birzu Gabriel , Matin Sakib , Hallatschek Oskar , Korolev Kirill S.
Published: March 2019

Theory predicts rapid genetic drift in expanding populations due to the serial founder effect at the expansion front. Yet, many natural populations maintain high genetic diversity in the newly colonized regions. Here, we investigate whether density-dependent dispersal could provide a resolution of this paradox. We find that genetic drift is dramatically suppressed when dispersal rates increase with the population density because many more migrants from the diverse, high-density regions arrive at the expansion edge. When density-dependence is weak or negative, the effective population size of the front scales only logarithmically with the carrying capacity. The dependence, however, switches to a sublinear power law and then to a linear increase as the density-dependence becomes strongly positive. To understand these results, we introduce a unified framework that predicts how the strength of genetic drift depends on the density-dependence in both dispersal and growth. This theory reveals that the transitions between different regimes of diversity loss are controlled by a single, universal parameter: the ratio of the expansion velocity to the geometric mean of dispersal and growth rates at expansion edge. Importantly, our results suggest that positive density-dependence could dramatically alter evolution in expanding populations even when its contributions to the expansion velocity is small.
An R Implementation of Tumor-Stroma-Immune Transcriptome Deconvolution Pipeline using DeMixT
Authors: Cao Shaolong , Wang Zeya , Gao Fan , Chen Jingxiao , Zhang Feng , Frigo Daniel E. , Efstathiou Eleni , Kopetz Scott , Wang Wenyi
Published: March 2019

The deconvolution of transcriptomic data from heterogeneous tissues in cancer studies remains challenging. Available software faces difficulties for accurately estimating both component-specific proportions and expression profiles for individual samples. To address these challenges, we present a new R-implementation pipeline for the more accurate and efficient transcriptome deconvolution of high dimensional data from mixtures of more than two components. The pipeline utilizes the computationally efficient DeMixT R-package with OpenMP and additional cancer-specific biological information to perform three-component deconvolution without requiring data from the immune profiles. It enables a wide application of DeMixT to gene expression datasets available from cancer consortium such as the Cancer Genome Atlas (TCGA) projects, where, other than the mixed tumor samples, a handful of normal samples are profiled in multiple cancer types. We have applied this pipeline to two TCGA datasets in colorectal adenocarcinoma (COAD) and prostate adenocarcinoma (PRAD). In COAD, we found varying distributions of immune proportions across the Consensus Molecular Subtypes, from the highest to the lowest being CMS1, CMS3, CMS4 and CMS2. In PRAD, we found the immune proportions are associated with progression-free survival (p<0.01) and negatively correlated with Gleason scores (p<0.001). Our DeMixT-centered analysis protocol opens up new opportunities to investigate the tumor-stroma-immune microenvironment, by providing both proportions and component-specific expressions, and thus better define the underlying biology of cancer progression.

Availability and implementation: An R package, scripts and data are available: https://github.com/wwylab/DeMixTallmaterials.
MicroRNA-138 negatively regulates the hypoxia-inducible factor 1α to suppress melanoma growth and metastasis
Authors: Qiu Haijiang , Chen Fangchao , Chen Minjun
Published: March 2019

Melanoma with rapid progression towards metastasis becomes the deadliest form of skin cancer. However, the mechanism of melanoma growth and metastasis is still unclear. Here, we found that miRNA-138 was low expression and hypoxia-inducible factor 1α (HIF1α) was high expression in the patient’s melanoma tissue, and they had a significant negative correlation (r = -0.937, P < 0.001). Patients with miRNA-138low/HIF1αhigh signature were predominant in late stage. Further, bioinformatic analysis demonstrated that miRNA-138 directly targeted HIF1α. We found that the introduction of miRNA-138 mimics to A375 cells could reduced HIF1α mRNA expression, and suppressed the cell proliferation, migration and invasion. Overexpression of miRNA-138 or inhibition of HIF1α significantly suppressed the growth and metastasis of melanoma in vivo. Our study demonstrates the role and clinical relevance of miRNA-138 and HIF1α in melanoma cell growth and metastasis, providing a novel therapeutic target for suppression of melanoma growth and metastasis.
How helpful are the protein-protein interaction databases and which ones?
Authors: Bajpai Akhilesh Kumar , Davuluri Sravanthi , Tiwary Kriti , Narayanan Sithalechumi , Oguru Sailaja , Basavaraju Kavyashree , Dayalan Deena , Thirumurugan Kavitha , Acharya Kshitish K
Published: March 2019

Protein-protein interactions (PPIs) are critical, and so are the databases and tools (resources) concerning PPIs. But in absence of systematic comparisons, biologists/bioinformaticians may be forced to make a subjective selection among such protein interaction databases and tools. In fact, a comprehensive list of such bioinformatics resources has not been reported so far. For the first time, we compiled 375 PPI resources, short-listed and performed preliminary comparison of 125 important ones (both lists available publicly at startbioinfo.com), and then systematically compared human PPIs from 16 carefully-selected databases. General features have been first compared in detail. The coverage of ‘experimentally verified’ vs. all PPIs, as well as those significant in case of disease-associated and other types of genes among the chosen databases has been compared quantitatively. This has been done in two ways: outputs manually obtained using web-interfaces, and all interactions downloaded from the databases. For the first approach, PPIs obtained in response to gene queries using the web interfaces were compared. As a query set, 108 genes associated with different tissues (specific to kidney, testis, and uterus, and ubiquitous) or diseases (breast cancer, lung cancer, Alzheimer’s, cystic fibrosis, diabetes, and cardiomyopathy) were chosen. PPI-coverage for well-studied genes was also compared with that of less-studied ones. For the second approach, the back-end-data from the databases was downloaded and compared. Based on the results, we recommend the use of STRING and UniHI for retrieving the majority of ‘experimentally verified’ protein interactions, and hPRINT and STRING for obtaining maximum number of ‘total’ (experimentally verified as well as predicted) PPIs. The analysis of experimentally verified PPIs found exclusively in each database revealed that STRING contributed about 71% of exclusive hits. Overall, hPRINT, STRING and IID together retrieved ~94% of ‘total’ protein interactions available in the databases. The coverage of certain databases was skewed for some gene-types. The results also indicate that the database usage frequency may not correlate with their advantages, thereby justifying the need for more frequent studies of this nature.
HSV-1 single cell analysis reveals anti-viral and developmental programs activation in distinct sub-populations
Authors: Drayman Nir , Patel Parthiv , Vistain Luke , Tay Savaş
Published: March 2019

Viral infection is usually studied at the population level by averaging over millions of cells. However, infection at the single-cell level is highly heterogeneous. Here, we combine live-cell imaging and single-cell RNA sequencing to characterize viral and host transcriptional heterogeneity during HSV-1 infection of primary human cells. We find extreme variability in the level of viral gene expression among individually infected cells and show that they cluster into transcriptionally distinct sub-populations. We find that anti-viral signaling is initiated in a rare group of abortively infected cells, while highly infected cells undergo cellular reprogramming to an embryonic-like transcriptional state. This reprogramming involves the recruitment of beta-catenin to the host nucleus and viral replication compartments and is required for late viral gene expression and progeny production. These findings uncover the transcriptional differences in cells with variable infection outcomes and shed new light on the manipulation of host pathways by HSV-1.
A cis-regulatory change underlying the motor neuron-specific loss of terminal selector gene expression in immotile tunicate larvae
Authors: Lowe Elijah K. , Racioppi Claudia , Peyriéras Nadine , Ristoratore Filomena , Christiaen Lionel , Swalla Billie J. , Stolfi Alberto
Published: March 2019

The evolutionary history of animal body plans cannot be fully reconstructed without considering the roles of both novelties and losses. Some of the more remarkable examples of massively parallel evolutionary losses in animals comes from many species in the tunicate genusMolgulathat have independently lost the swimming larva and instead develop as tail-less, immotile larvae that bypass the period of swimming and dispersal observed in other tunicates, marine invertebrate chordates that alternate between motile larval and sessile adult life cycle stages. The larvae ofMolgula occultaand other tail-less species do not fully develop structures that are essential for swimming behavior, including notochord, tail muscles, and otolith, and loss-of-function mutations have been identified in various genes required for the differentiation of these tissues. However, little is known about the extent of development of the larval nervous system inM. occulta. While differentiated neurons might in principle be entirely dispensable to the non-swimming larva, the adult has a fully functional nervous system like any other tunicate. To further investigate this conundrum, we studied the specification and patterning of theM. occultaMotor Ganglion, which is the key central nervous system compartment that drives the motor movements of swimming tunicate larvae. We found that the expression patterns of important regulators of MG neuron subtype specification are highly conserved during the development of the non-swimming larvae ofM. occulta, suggesting that the gene networks regulating their expression are largely intact in this species, despite the loss of swimming ability. However, we identified aM. occulta-specific reduction in expression of the important motor neuron terminal selector geneEbf (Collier/Olf/EBF or COE)in the Motor Ganglion. AlthoughM. occulta Ebfis predicted to encode a fully functional protein, its expression was reduced in developing motor neurons when compared to species with swimming larvae, which was corroborated by measuring allele-specific expression ofEbfin interspecific hybrid embryos produced by crossingM. occultawith the closely related swimming speciesM. oculata. Comparative reporter construct experiments also revealed a specificcis-regulatory sequence change that underlies the reduced expression ofM. occulta Ebfin motor neurons, but not in other tissues and cell types. This points to a potential mechanism for arresting larval motor neuron differentiation in the non-swimming larvae of this species.
FSTand the Triangle Inequality for Biallelic Markers
Authors: Arbisser Ilana M. , Rosenberg Noah A.
Published: March 2019

The population differentiation statisticFST, introduced by Sewall Wright, is often treated as a pairwise distance measure between populations. As was known to Wright, however,FSTis not a true metric because allele frequencies exist for which it does not satisfy the triangle inequality. We prove that a stronger result holds: for biallelic markers whose allele frequencies differ across three populations,FSTneversatisfies the triangle inequality. We study the deviation from the triangle inequality as a function of the allele frequencies of three populations, identifying frequency vectors at which the deviation is maximal. We also examine the implications of the failure of the triangle inequality for the four-point condition for groups of four populations. Next, we examine the extent to whichFSTfails to satisfy the triangle inequality in genome-wide data from human populations, finding that some loci have frequencies that produce deviations near the maximum. We discuss the consequences of the theoretical results for various types of data analysis, including multidimensional scaling and inference of neighbor-joining trees from pairwiseFSTmatrices.
Multiple constrained minimum variance beamformer (MCMV) performance in connectivity analyses
Authors: Nunes Adonay S. , Moiseev Alexander , Kozhemiako Nataliia , Cheung Teresa , Ribary Urs , Doesburg Sam M.
Published: March 2019

Functional brain connectivity is increasingly being seen as critical for cognition, perception and motor control.Magnetoencephalography and electroencephalography are modalities that offer noninvasive mapping of electrophysiological interactions among brain regions, yet suffer from signal leakage and signal cancellation when estimating brain activity. This leads to biased connectivity values which complicate interpretation. In this study, we test the hypothesis that a Multiple Constrained Minimum Variance beamformer (MCMV) outperforms the more traditional Linearly Constrained Minimum Variance beamformer (LCMV) for estimation of electrophysiological connectivity. To this end, MCMV and LCMV performance is compared in task related analyses with both simulated data and human MEG recordings of visual steady state signals, and in resting state analyses with simulated data and human MEG data of 89 subjects. In task related scenarios connectivity was estimated using coherence and phase locking values, whereas envelope correlations were used for the resting state data. We also introduce a novel Augmented Pairwise MCMV (APW-MCMV) approach for signal leakage suppression in resting state analyses and assess its performance against LCMV and more conventional MCMV approaches. We demonstrate that with MCMV effects of signal mixing and coherent source cancellation are greatly reduced in both task related and resting state conditions, while in contrast to other approaches 0-and short time lag interactions are preserved. In addition, we demonstrate that in resting state analyses, APW-MCMV strongly reduces spurious connections while better controlling for false negatives compared to more conservative measures such as symmetrical orthogonalization.
A Novel Transfer Learning Approach for Toxoplasma Gondii Microscopic Image Recognition by Fuzzy Cycle Generative Adversarial Network
Authors: Li Sen , Li Aijia , Lara Diego Alejandro Molina , Marín Jorge Enrique Gómez , Juhas Mario , Zhang Yang
Published: March 2019

Toxoplasma gondii, one of the world’s most common parasites, can infect all types of warm-blooded animals, including one-third of the world’s human population. Most current routine diagnostic methods are costly, time-consuming, and labor-intensive. AlthoughT.gondiican be directly observed under the microscope in tissue or spinal fluid samples, this form of identification is difficult and requires well trained professionals. Nevertheless, the traditional identification of parasites under the microscope is still performed by a large number of laboratories. Novel, efficient and reliable methods ofT.gondiiidentification are therefore needed, particularly in developing countries. To this end, we developed a novel transfer learning based microscopic image recognition method forT.gondiiidentification. This approach employs Fuzzy Cycle Generative Adversarial Network (FCGAN) with transfer learning utilizing knowledge gained by the parasitologists that Toxoplasma is in banana or crescent shaped form. Our approach aims to build connection between micro and macro associated objects by embedding fuzzy C-means cluster algorithm into Cycle Generative Adversarial Network (Cycle GAN). Our approach achieves 93.1% and 94.0% detection accuracy for 400X and 1000X Toxoplasma microscopic images respectively. We show the high accuracy and effectiveness of our approach in the newly collected unlabeled Toxoplasma microscopic images, comparing to other current available deep learning methods. This novel method for Toxoplasma microscopic image recognition will open a new window for developing cost-effective and scalable deep learning based diagnostic solution, potentially enabling broader clinical access in developing countries.
Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation
Authors: Vallianatos Christina N. , Raines Brynne , Porter Robert S. , Bonefas Katherine M. , Wu Michael C. , Garay Patricia M. , Collette Katie M. , Seo Young Ah , Dou Yali , Keegan Catherine E. , Tronson Natalie C. , Iwase Shigeki
Published: March 2019

Histone H3 lysine 4 methylation (H3K4me) is extensively regulated by numerous writer and eraser enzymes in mammals. Nine H3K4me enzymes are associated with neurodevelopmental disorders to date, indicating their important roles in the brain. However, interplay among H3K4me enzymes during brain development remains largely unknown. Here, we show functional interactions of a writer-eraser duo,KMT2AandKDM5C, which are responsible for Wiedemann-Steiner Syndrome (WDSTS), and mental retardation X-linked syndromic Claes-Jensen type (MRXSCJ), respectively. Despite opposite enzymatic activities, the two mouse models deficient for eitherKmt2aorKdm5cshared reduced dendritic spines and increased aggression. Double mutation ofKmt2aandKdm5cclearly reversed dendritic morphology, key behavioral traits including aggression, and partially corrected altered transcriptomes and H3K4me landscapes. Thus, our study uncovers common yet mutually suppressive aspects of the WDSTS and MRXSCJ models and provides a proof of principle for balancing a single writer-eraser pair to ameliorate their associated disorders.
Comprehensive analysis of the internal structure and firmness in American cranberry (Vaccinium macrocarponAit.) fruit
Authors: Diaz-Garcia Luis , Rodriguez-Bonilla Lorraine , Phillips Matthew , Lopez-Hernandez Arnoldo , Grygleski Edward , Atucha Amaya , Zalapa Juan
Published: March 2019

Cranberry (Vaccinium macrocarponAit.) fruit quality traits encompass many properties. Among these, fruit firmness has become a quality standard due to the recent demand increase for sweetened and dried cranberries (SDC). Traditionally, this trait has been measured by the cranberry industry using compression tests; however, it is poorly understood how fruit firmness is influenced by other characteristics. In this study, we developed a high-throughput computer-vision method to measure the internal structure of cranberry fruit, which may in turn influence cranberry fruit firmness. We measured the internal structure of 16 cranberry cultivars measured over a 40-day period. Internal structure data paired with fruit firmness values at each evaluation period allowed us to explore the correlations between firmness and internal morphological characteristics.
Evolutionary changes of an intestinalLactobacillus reuteriduring probiotic manufacture
Authors: López Lázaro , Cardenas Paúl , Prado María B. , Trueba Gabriel
Published: March 2019

Probiotic bacteria are frequently used to treat intestinal (and other types of diseases) or to improve health, however little is known about the evolutionary changes of these bacteria during probiotic manufacture. It has been observed that when bacteria adapt to a new environment, they lose the skills to thrive in the original niche. In this study, a strain ofLactobacillus reuteriwas isolated from the duodenum of a mouse and subjected to 150 serial passes in milk to simulate industrial propagation of probiotic bacteria. The strain adapted to milk outperformed its ancestor in milk, but it showed reduced aptitude to grow culture media, and possibly in mouse intestines. Bacterial adaptation to milk seemed to select a number of non-synonymous mutations in metabolic genes.

IMPORTANCE

Bacteria in the microbiota must endure hostile conditions including antagonism from other members of the microbial community. Little is known about the evolution of probiotic bacteria in the dairy industry. We show that repeated growth ofL. reuteriin milk results in reduced ability to grow in culture medium and possibly colonize the mammalian intestine. Our results contribute to the notion that probiotic bacteria colonize only transiently intestines.
The phytopathogenic nature ofDickeya aquatica174/2 and the dynamic early evolution ofDickeyapathogenicity
Authors: Duprey Alexandre , Taib Najwa , Leonard Simon , Garin Tiffany , Flandrois Jean-Pierre , Nasser William , Brochier-Armanet Céline , Reverchon Sylvie
Published: March 2019

Originality-Significance statement

Although the reach of large-scale comparative studies has spread exponentially over the years, the phytopathogenicDickeyagroup remains overlooked. In this work, we sequence the complete genome ofDickeya aquaticatype strain, a species isolated from water that was first assumed to be non-phytopathogenic. We show that the proteome ofD. aquaticacontains a wide number of proteins involved inDickeyavirulence, including plant cell wall degrading enzymes, suggesting that this species could be in fact pathogenic. Using experimental approaches, we confirm this prediction and uncover the particular affinity ofD. aquaticafor acidic fruits. In-depth phylogenomic analyses reveal thatDickeyaspecies display a great degree of genetic plasticity in the pathogenicity determinants, explaining how this bacterial group was able to colonize a wide variety of plants growing in different climates. These observations greatly advance our understanding of how bacteria adapt to new ecological niches.

Dickeyais a genus of phytopathogenic enterobacterales causing soft rot in a variety of plants (e.g. potato, chicory, maize). Among the species affiliated to this genus,Dickeya aquatica, described in 2014, remained particularly mysterious because it had no known host. Furthermore, whileD. aquaticawas proposed to represent a deep-branching species amongDickeyagenus, its precise phylogenetic position remained elusive.

Here, we report the complete genome sequence of theD. aquaticatype strain 174/2. We demonstrate the affinity ofD. aquaticaTfor acidic fruits such as tomato and cucumber, and show that exposure of this bacterium to acidic pH induces twitching motility. An in-depth phylogenomic analysis of all availableDickeyaproteomes pinpointsD. aquaticaas the second deepest branching lineage within this genus and reclassifies two lineages that likely correspond to new genomospecies (gs.):Dickeyags. poaceaephila (Dickeyasp NCPPB 569) andDickeyags. undicola (Dickeyasp 2B12), together with a new putative genus, tentatively namedProdigiosinella. Finally, from comparative analyses ofDickeyaproteomes we infer the complex evolutionary history of this genus, paving the way to study the adaptive patterns and processes ofDickeyato different environmental niches and hosts. In particular, we hypothetize that the lack of xylanases and xylose degradation pathways inD. aquaticacould reflects adaptation to aquatic charophyte hosts which, in contrast to land plants, do not contain xyloglucans.