bluuebunny/crossref_metadata_2025 huggingface dataset:
Metagenome-Assembled Genome Binning Methods with Short Reads Disproportionately Fail for Plasmids and Genomic Islands
Authors: Maguire Finlay , Jia Baofeng , Gray Kristen , Lau Wing Yin Venus , Beiko Robert G. , Brinkman Fiona S.L.
Published: April 2020

Metagenomic methods are an important tool in the life sciences, as they enable simultaneous characterisation of all microbes in a community without time-consuming and bias-inducing culturing. Metagenome-assembled genome (MAG) binning methods have emerged as a promising approach to recover individual genomes from metagenomic data. However, MAG binning has not been well assessed for its ability to recover mobile genetic elements (MGEs), such as plasmids and genomic islands (GIs), that have very high clinical/agricultural/environmental importance. Certain antimicrobial resistance (AMR) genes and virulence factor (VF) genes are noted to be disproportionately associated with MGEs, making studying their transmission a public health priority. However, the variable copy number and sequence composition of MGEs relative to the majority of the host genome makes them potentially problematic for MAG binning methods. To systematically investigate this, we simulated a low-complexity metagenome comprising 30 GI-rich and plasmid-containing bacterial genomes. MAGs were then recovered using 12 current prediction pipelines and evaluated for recovery of MGE-associated AMR/VF genes. Here we show that while 82-94% of chromosomes could be correctly recovered and binned, only 38-44% of GIs were recovered and, even more notably, only 1-29% of plasmid sequences were found. Most strikingly, no plasmid-borne VF or AMR genes were recovered and within GIs, only between 0-45% of AMR or VF genes were identified. We conclude that short-read MAGs are largely ineffective for the analysis of mobile genes, including those of public-health importance like AMR and VF genes. We propose that microbiome researchers should instead primarily utilise unassembled short reads and/or long-read approaches to more accurately analyse metagenomic data
Dynamic structural order of a low complexity domain facilitates assembly of intermediate filaments
Authors: Sysoev Vasily O. , Kato Masato , Sutherland Lillian , Hu Rong , McKnight Steven L. , Murray Dylan T.
Published: April 2020

The coiled-coil domains of intermediate filament (IF) proteins are flanked by regions of low sequence complexity. Whereas IF coiled-coil domains assume dimeric and tetrameric conformations on their own, maturation of eight tetramers into cylindrical IFs is dependent upon either “head” or “tail” domains of low sequence complexity. Here we confirm that the tail domain required for assembly ofDrosophilaTm1 IFs functions by forming labile cross-β interactions. These interactions are seen in polymers made from the tail domain alone as well as assembled IFs formed by the intact Tm1 protein. The ability to visualize such interactionsin situwithin the context of a discrete cellular assembly lends support to the concept that equivalent interactions may be used in organizing other dynamic aspects of cell morphology.

One Sentence Summary

A new form of protein folding that interconverts between the structured and unstructured states controls assembly of intermediate filaments.
A demogenetic individual based model for the evolution of traits and genome architecture under sexual selection
Authors: Chevalier Louise , De Coligny François , Labonne Jacques
Published: April 2020

Sexual selection has long been known to favor the evolution of mating behaviors such as mate preference and competitiveness, and to affect their genetic architecture, for instance by favoring genetic correlation between some traits. Reciprocally, genetic architecture can affect the expression and the evolvability of traits and mating behaviors. But sexual selection is highly context-dependent, making interactions between individuals a central process in evolution, governing the transmission of genotypes to the next generation. This loop between the genetic structure conditioning the expression and evolution of traits and behaviour, and the feedback of this phenotypic evolution on the architecture of the genome in the dynamic context of sexual selection, has yet to be thoroughly investigated. We argue that demogenetic agent-based models (DG-ABM) are especially suited to tackle such a challenge because they allow explicit modelling of both the genetic architecture of traits and the behavioural interactions in a dynamic population context. We here present a DG-ABM able to simultaneously track individual variation in traits (such as gametic investment, preference, competitiveness), fitness and genetic architecture throughout evolution. Using two simulation experiments, we compare various mating systems and show that behavioral interactions during mating triggered some complex feedback in our model, between fitness, population demography, and genetic architecture, placing interactions between individuals at the core of evolution through sexual selection. DG-ABMs can, therefore, relate to theoretical patterns expected at the population level from simpler analytical models in evolutionary biology, and at the same time provide a more comprehensive framework regarding individual trait and behaviour variation, that is usually envisioned separately from genome architecture in behavioural ecology.
A novel CRISPR-based malaria diagnostic capable ofPlasmodiumdetection, speciation, and drug-resistance genotyping
Authors: Cunningham CH , Hennelly CM , Lin JT , Ubalee R , Boyce RM , Mulogo EM , Hathaway N , Thwai KL , Phanzu F , Kalonji A , Mwandagalirwa K , Tshefu A , Meshnick SR , Juliano JJ , Parr JB
Published: April 2020

CRISPR-based diagnostics are a new class of highly sensitive and specific assays with multiple applications in infectious disease diagnosis. SHERLOCK, or Specific High-Sensitivity Enzymatic Reporter UnLOCKing, is one such CRISPR-based diagnostic that combines recombinase polymerase pre-amplification, CRISPR-RNA base-pairing, and LwCas13a activity for nucleic acid detection. We developed SHERLOCK assays for malaria capable of detecting allPlasmodiumspecies known to cause malaria in humans and species-specific detection ofP. vivaxandP. falciparum, the species responsible for the majority of malaria cases worldwide. We validated these assays against parasite genomic DNA and achieved analytical sensitivities ranging from 2.5-18.8 parasites per reaction. We further tested these assays using a diverse panel of 123 clinical samples from the Democratic Republic of the Congo, Uganda, and Thailand and pools ofAnophelesmosquitoes from Thailand. When compared to real-time PCR, theP. falciparumassay achieved 94% sensitivity and 94% specificity in clinical samples. In addition, we developed a SHERLOCK assay capable of detecting the dihydropteroate synthetase (dhps) single nucleotide variant A581G associated withP. falciparumsulfadoxine-pyrimethamine resistance. Compared to amplicon-based deep sequencing, thedhpsSHERLOCK assay achieved 73% sensitivity and 100% specificity when applied to a panel of 43 clinical samples, with false-negative calls only at lower parasite densities. These novel SHERLOCK assays have potential to spawn a new generation of molecular diagnostics for malaria and demonstrate the versatility of CRISPR-based diagnostic approaches.

One-sentence summary

Novel malaria SHERLOCK assays enabled robust detection, speciation, and genotyping ofPlasmodium spp. in diverse samples collected in Africa and Asia.
aradeepopsis: From images to phenotypic traits using deep transfer learning
Authors: Hüther Patrick , Schandry Niklas , Jandrasits Katharina , Bezrukov Ilja , Becker Claude
Published: April 2020

Linking plant phenotype to genotype, i.e., identifying genetic determinants of phenotypic traits, is a common goal of both plant breeders and geneticists. While the ever-growing genomic resources and rapid decrease of sequencing costs have led to enormous amounts of genomic data, collecting phenotypic data for large numbers of plants remains a bottleneck. Many phenotyping strategies rely on imaging plants, which makes it necessary to extract phenotypic measurements from these images rapidly and robustly. Common image segmentation tools for plant phenotyping mostly rely on color information, which is error-prone when either background or plant color deviate from the underlying expectations. We have developed a versatile, fully open-source pipeline to extract phenotypic measurements from plant images in an unsupervised manner.aradeepopsiswas built around the deep-learning model DeepLabV3+ that was re-trained for segmentation ofArabidopsis thalianarosettes. It uses semantic segmentation to classify leaf tissue into up to three categories: healthy, anthocyanin-rich, and senescent. This makesaradeepopsisparticularly powerful at quantitative phenotyping from early to late developmental stages, of mutants with aberrant leaf color and/or phenotype, and of plants growing in stressful conditions where leaf color may deviate from green. Using our tool on a panel of 210 natural Arabidopsis accessions, we were able to not only accurately segment images of phenotypically diverse genotypes but also to map known loci related to anthocyanin production and early necrosis using thearadeepopsisoutput in genome-wide association analyses. Our pipeline is able to handle images of diverse origins, image quality, and background composition, and could even accurately segment images of a distantly related Brassicaceae. Because it can be deployed on virtually any common operating system and is compatible with several high-performance computing environments,aradeepopsiscan be used independently of bioinformatics expertise and computing resources.aradeepopsisis available athttps://github.com/Gregor-Mendel-Institute/aradeepopsis.
Robust Modelling of Additive and Non-additive Variation with Intuitive Inclusion of Expert Knowledge
Authors: Hem Ingeborg Gullikstad , Selle Maria Lie , Gorjanc Gregor , Fuglstad Geir-Arne , Riebler Andrea
Published: April 2020

We propose a novel Bayesian approach that robustifies genomic modelling by leveraging expert knowledge through prior distributions. The central component is the hierarchical decomposition of phenotypic variation into additive and non-additive genetic variation, which leads to an intuitive model parameterization that can be visualised as a tree. The edges of the tree represent ratios of variances, for example broad-sense heritability, which are quantities for which expert knowledge is natural to exist. Penalized complexity priors are defined for all edges of the tree in a bottom-up procedure that respects the model structure and incorporates expert knowledge through all levels. We investigate models with different sources of variation and compare the performance of different priors implementing varying amounts of expert knowledge in the context of plant breeding. A simulation study shows that the proposed priors implementing expert knowledge improve the robustness of genomic modelling and the selection of the genetically best individuals in a breeding program. We observe this improvement in both variety selection on genetic values and parent selection on additive values; the variety selection benefited the most. In a real case study expert knowledge increases phenotype prediction accuracy for cases in which the standard maximum likelihood approach did not find optimal estimates for the variance components. Finally, we discuss the importance of expert knowledge priors for genomic modelling and breeding, and point to future research areas of easy-to-use and parsimonious priors in genomic modelling.
miR-183/96/182 cluster is an important morphogenetic factor targetingPAX6expression in differentiating human retinal organoids
Authors: Peskova Lucie , Jurcikova Denisa , Vanova Tereza , Krivanek Jan , Capandova Michaela , Sramkova Zuzana , Kolouskova Magdalena , Kotasova Hana , Streit Libor , Barta Tomas
Published: April 2020

MicroRNAs (miRNAs), a class of small, non-coding RNA molecules represent important regulators of gene expression. Recent reports have implicated their role in the cell specification process acting as “fine-tuners” to ensure the precise gene expression at the specific stage of cell differentiation. Here we used retinal organoids differentiated from human pluripotent stem cells (hPSCs) as a model to closely investigate the role of a sensory organ-specific and evolutionary conserved miR-183/96/182 cluster. Using a miRNA tough decoy approach, we inhibited the miR-183/96/182 cluster in hPSCs. Inhibition of the miRNA cluster resulted in an increased expansion of neuroepithelium leading to abnormal “bulged” neural retina in organoids, associated with upregulation of neural-specific and retinal-specific genes. Importantly, we identifiedPAX6, a well-known essential gene in neuroectoderm specification, as a target of the miR-183/96/182 cluster members. Taken together, the miR-183/96/182 cluster not only represents an important regulator ofPAX6expression, but it also plays a crucial role in retinal tissue morphogenesis.
A Pan-cancer Blueprint of the Heterogeneous Tumour Microenvironment Revealed by Single-Cell Profiling
Authors: Qian Junbin , Olbrecht Siel , Boeckx Bram , Vos Hanne , Laoui Damya , Etlioglu Emre , Wauters Els , Pomella Valentina , Verbandt Sara , Busschaert Pieter , Bassez Ayse , Franken Amelie , Bempt Marlies Vanden , Xiong Jieyi , Weynand Birgit , van Herck Yannick , Antoranz Asier , Bosisio Francesca Maria , Thienpont Bernard , Floris Giuseppe , Vergote Ignace , Smeets Ann , Tejpar Sabine , Lambrechts Diether
Published: April 2020

Abstract

The stromal compartment of the tumour microenvironment consists of a heterogeneous set of tissue-resident and tumour-infiltrating cells, which are profoundly moulded by cancer cells. An outstanding question is to what extent this heterogeneity is similar between cancers affecting different organs. Here, we profile 233,591 single cells from patients with lung, colorectal, ovary and breast cancer (n=36) and construct a pan-cancer blueprint of stromal cell heterogeneity using different single-cell RNA and protein-based technologies. We identify 68 stromal cell populations, of which 46 are shared between cancer types and 22 are unique. We also characterise each population phenotypically by highlighting its marker genes, transcription factors, metabolic activities and tissue-specific expression differences. Resident cell types are characterised by substantial tissue specificity, while tumour-infiltrating cell types are largely shared across cancer types. Finally, by applying the blueprint to melanoma tumours treated with checkpoint immunotherapy and identifying a naïve CD4+T-cell phenotype predictive of response to checkpoint immunotherapy, we illustrate how it can serve as a guide to interpret scRNA-seq data. In conclusion, by providing a comprehensive blueprint through an interactive web server, we generate a first panoramic view on the shared complexity of stromal cells in different cancers.
Significant Shortest Paths For The Detection Of Putative Disease Modules
Authors: Pepe Daniele
Published: April 2020

Background

The characterization of diseases in terms of perturbated gene modules was recently introduced for the analysis of gene expression data. Some approaches were proposed in literature, but many times they are inductive approaches. This means that starting directly from data, they try to infer key gene networks potentially associated to the biological phenomenon studied. However they ignore the biological information already available to characterize the gene modules. Here we propose the detection of perturbed gene modules using the combination of data driven and hypothesis-driven approaches relying on biological metabolic pathways and significant shortest paths tested by structural equation modeling.

The procedure was tested on microarray experiments relative to infliximab response in patients with inflammatory bowel disease. Starting from differentially expressed genes (DEGs) and pathway analysis, significant shortest paths between DEGs were found and merged together. The validation of the final disease module was principally done by the comparison of genes in the module with those already associated with the disease, using the Wang similarity semantic index, and enrichment analysis based on Disease Ontology. Finally a topological analysis of the module via centrality measures and the identification of the cut vertices, allowed to unveil important nodes in the network as the TNF gene, and other potential drug target genes as p65 and PTPN6.

Conclusions

Here we propose a downstream method for the characterization of disease modules from gene expression data. The core of the method is rooted on the identification of significant shortest paths between DEGs by structural equation modeling. This allows to have a mix approach based on data and biological knowledge enclosed in biological pathways. Other methods here described as enrichment analysis and topological analysis were functional to the validation of the procedure. The results obtained were promising, considering the genes and their connections found in the putative disease modules.
Design and power analysis for multi-sample single cell genomics experiments
Authors: Schmid Katharina T. , Cruceanu Cristiana , Böttcher Anika , Lickert Heiko , Binder Elisabeth B. , Theis Fabian J. , Heinig Matthias
Published: April 2020

Background

The identification of genes associated with specific experimental conditions, genotypes or phenotypes through differential expression analysis has long been the cornerstone of transcriptomic analysis. Single cell RNA-seq is revolutionizing transcriptomics and is enabling interindividual differential gene expression analysis and identification of genetic variants associated with gene expression, so called expression quantitative trait loci at cell-type resolution. Current methods for power analysis and guidance of experimental design either do not account for the specific characteristics of single cell data or are not suitable to model interindividual comparisons.

Results

Here we present a statistical framework for experimental design and power analysis of single cell differential gene expression between groups of individuals and expression quantitative trait locus analysis. The model relates sample size, number of cells per individual and sequencing depth to the power of detecting differentially expressed genes within individual cell types. Power analysis is based on data driven priors from literature or pilot experiments across a wide range of application scenarios and single cell RNA-seq platforms. Using these priors we show that, for a fixed budget, the number of cells per individual is the major determinant of power.

Conclusion

Our model is general and allows for systematic comparison of alternative experimental designs and can thus be used to guide experimental design to optimize power. For a wide range of applications, shallow sequencing of high numbers of cells per individual leads to higher overall power than deep sequencing of fewer cells. The model is implemented as an R packagescPower.
Transmissible cancers and the evolution of sex under the Red Queen hypothesis
Authors: Aubier Thomas G. , Galipaud Matthias , Erten E. Yagmur , Kokko Hanna
Published: April 2020

The predominance of sexual reproduction in eukaryotes remains paradoxical in evolutionary theory. Of the hypotheses proposed to resolve this paradox, the “Red Queen hypothesis” emphasizes the potential of antagonistic interactions to cause fluctuating selection, which favours the evolution and maintenance of sex. While empirical and theoretical developments have focused on host-parasite interactions, the premises of the Red Queen theory apply equally well to any type of antagonistic interactions. Recently, it has been suggested that early multicellular organisms with basic anticancer defenses were presumably plagued by antagonistic interactions with transmissible cancers, and that this could have played a pivotal role in the evolution of sex. Here, we dissect this argument using a population genetic model. One fundamental aspect distinguishing transmissible cancers from other parasites is the continual production of cancerous cell lines from hosts’ own tissues. We show that this influx dampens fluctuating selection and therefore makes the evolution of sex more difficult than in standard Red Queen models. Although coevolutionary cycling can remain sufficient to select for sex under some parameter regions of our model, we show that the size of those regions shrinks once we account for epidemiological constraints. Altogether, our results suggest that horizontal transmission of cancerous cells is unlikely to cause fluctuating selection favouring sexual reproduction. Nonetheless, we confirm that vertical transmission of cancerous cells can promote the evolution of sex through a separate mechanism, known as similarity selection, that does not depend on coevolutionary fluctuations.
Codingde novomutations identified by WGS reveal novel orofacial cleft genes
Authors: Bishop Madison R. , Perez Kimberly Diaz , Sun Miranda , Ho Samantha , Chopra Pankaj , Mukhopadhyay Nandita , Hetmanski Jacqueline B. , Taub Margaret A. , Moreno-Uribe Lina M. , Valencia-Ramirez Luz Consuelo , Restrepo Muñeton Claudia P. , Wehby George , Hecht Jacqueline T. , Deleyiannis Frederic , Weinberg Seth M. , Wu-Chou Yah Huei , Chen Philip K. , Brand Harrison , Epstein Michael P. , Ruczinski Ingo , Murray Jeffrey C. , Beaty Terri H. , Feingold Eleanor , Lipinski Robert J. , Cutler David J. , Marazita Mary L. , Leslie Elizabeth J.
Published: April 2020

Whilede novomutations (DNMs) are known to increase risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 case-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.
Site-specific covalent labeling of large RNAs with nanoparticles empowered by expanded genetic alphabet transcription
Authors: Wang Yan , Chen Yaoyi , Hu Yanping , Fang Xianyang
Published: April 2020

Conjugation of RNAs with nanoparticles is of significant importance for its numerous applications in biology and medicine, which however remains challenging, especially for large ones. So far, the majority of RNA labeling rely on solid-phase chemical synthesis, which is generally limited to RNAs smaller than 100 nts. We here present an efficient and generally applicable labeling strategy for site-specific covalent conjugation of large RNAs with gold nanoparticle (AuNP) empowered by expanded genetic alphabet transcription. We synthesize an amine-derivatized TPT3 (TPT3A), which are site-specifically incorporated into a 97-nt 3’SL RNA and a 719-nt mini genomic RNA (DENV-mini) from Dengue virus serotype 2 (DENV2) by standardin vitrotranscription with expanded genetic alphabet containing the A-T, G-C natural base pairs and the TPT3-NaM unnatural base pair. TPT3 modification cause minimal structural perturbations to the RNAs by small angle X-ray scattering. The purified TPT3A-modified RNAs are covalently conjugated with mono-Sulfo-NHS-Nanogold nanoparticlesviathe highly selective amine-NHS ester reaction and purified under non-denaturing conditions. We demonstrate the application of the AuNP-RNA conjugates in large RNA structural biology by an emerging molecular ruler, X-ray scattering interferometry (XSI). The inter-nanoparticle distance distributions in the 3’SL and DENV-mini RNAs derived from XSI measurements support the hypothetical model of flavivirus genome circularization, thus validate the applicability of this novel labeling strategy. The presented strategy overcomes the size constraints in conventional RNA labeling strategies, and is expected to have wide applications in large RNA structural biology and RNA nanotechnology.

Significance Statement

We present a site-specific labeling strategy for large RNAs by T7 transcription with expanded genetic alphabet containing TPT3-NaM unnatural base pair. The applicability of this labeling strategy is validated by X-ray scattering interferometry measurements on a 97-nt and a 719-nt RNAs. This strategy can be applicable to natural RNAs or artificial RNA nanostructures with sizes from tens up to thousands of nucleotides, or covalent conjugation of RNAs with other metal nanoparticles. The usage of a far upstream forward primer during PCR enables easy purification of RNA from DNA templates, the non-denaturing conditions for conjugation reactions and purification avoids potential large RNA misfolding. This labeling strategy expands our capability to site-specifically conjugate RNA with nanoparticles for many applications.
Distinct trends in chemical composition of proteins from metagenomes in redox and salinity gradients
Authors: Dick Jeffrey M. , Yu Miao , Tan Jingqiang
Published: April 2020

Thermodynamic influences on the chemical compositions of proteins have remained enigmatic despite much work that demonstrates the impact of environmental conditions on amino acid frequencies. Here, we show that the dehydrating effect of salinity is apparent in protein sequences inferred from metagenomes and metatranscriptomes. The stoichiometric hydration state (nH2O), derived from the number of water molecules in theoretical reactions to form proteins from a particular set of basis species (glutamine, glutamic acid, cysteine, O2, H2O), decreases along salinity gradients including the Baltic Sea, Amazon River and ocean plume, and other samples from freshwater and marine environments. Analysis of other metagenomic datasets shows that differences in carbon oxidation state, rather than stoichiometric hydration state, are a stronger indicator of redox gradients than salinity gradients. These compositional metrics can help to identify thermodynamic effects in the distribution of proteins along chemical gradients at scales from geologic systems to cells.
Limited Dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transduction
Authors: Kan Wei , Enos Michael , Korkmazhan Elgin , Muennich Stefan , Chen Dong-Hua , Gammons Melissa V. , Vasishtha Mansi , Bienz Mariann , Dunn Alexander R. , Skiniotis Georgios , Weis William I.
Published: April 2020

In Wnt/β-catenin signaling, the transcriptional coactivator β-catenin is regulated by its phosphorylation in a complex that includes the scaffold protein Axin and associated kinases. Wnt binding to its coreceptors activates the cytosolic effector Dishevelled (Dvl), leading to the recruitment of Axin and the inhibition of β-catenin phosphorylation. This process requires interaction of homologous DIX domains present in Dvl and Axin, but is mechanistically undefined. We show that Dvl DIX forms antiparallel, double-stranded oligomersin vitro, and that Dvl in cells forms oligomers typically <10 molecules at endogenous expression levels. Axin DIX (DAX) forms small single-stranded oligomers, but its self-association is stronger than that of DIX. DAX caps the ends of DIX oligomers, such that a DIX oligomer has at most four DAX binding sites. The relative affinities and stoichiometry of the DIX-DAX interaction provide a mechanism for efficient inhibition of β-catenin phosphorylation upon Axin recruitment to the Wnt receptor complex.
Membrane tension can enhance adaptation to maintain polarity of migrating cells
Authors: Zmurchok C. , Collette J. , Rajagopal V. , Holmes W. R.
Published: April 2020

Migratory cells are known to adapt to environments that contain wide-ranging levels of chemoattractant. While biochemical models of adaptation have been previously proposed, here we discuss a different mechanism based on mechanosensing, where the interaction between biochemical signaling and cell tension facilitates adaptation. We describe and analyze a model of mechanochemical-based adaptation coupling a mechanics-based physical model of cell tension coupled with the wave-pinning reaction-diffusion model for Rac activity. Mathematical analysis of this model, simulations of a simplified 1D cell geometry, and 2D finite element simulations of deforming cells reveal that as a cell protrudes under the influence of high stimulation levels, tension mediated inhibition of GTPase signaling causes the cell to polarize even when initially over-stimulated. Specifically, tension mediated inhibition of GTPase activation, which has been experimentally observed in recent years, facilitates this adaptation by countering the high levels of environmental stimulation. These results demonstrate how tension related mechanosensing may provide an alternative (and potentially complementary) mechanism for cell adaptation.

Statement of Significance

Migratory cells such as human neutrophils encounter environments that contain wide-ranging levels of chemoattractant. In order to move, these cells must maintain an organized front-rear signaling polarity despite this wide variation in environmental stimuli. Past research has demonstrated a number of biochemical based mechanisms by which cells adapt to variable signal levels. Here we demonstrate that the interplay between Rho GTPase signaling and tension mediated feedbacksmayprovide an alternative mechanochemical mechanism for adaptation to high levels of signaling.
From pathogen to commensal to probiotic: modification ofMicrobacterium nematophilum-C. elegansinteraction during chronic infection by the absence of host insulin signalling
Authors: Gravato-Nobre Maria , Hodgkin Jonathan , Ligoxygakis Petros
Published: April 2020

The nematode wormCaenorhabditis elegansdepends on microbes in decaying vegetation as its food source. To survive in an environment rich in opportunistic pathogens,C. eleganshas evolved an epithelial defence system where surface-exposed tissues such as epidermis, pharynx, intestine, vulva and hindgut have the capacity of eliciting appropriate immune defences to acute gut infection. However, it is unclear how the worm responds to chronic intestinal infections. To this end, we have surveyedC. elegansmutants that are involved in inflammation, immunity and longevity to find their phenotypes during chronic infection. Worms that grew in a monoculture of the natural pathogenMicrobacterium nematophilum(CBX102 strain) had a reduced lifespan and health span. This was independent of intestinal colonisation as both CBX102 and the derived avirulent strain UV336 were early persistent colonisers. In contrast, long-liveddaf-2mutants were resistant to chronic infection, showing reduced colonisation and a higher age-dependent vigour. In fact, UV336 acted as a probiotic indaf-2, showing a lifespan extension beyond OP50, theE. colistrain used for laboratoryC. elegansculture. Longevity and vigour ofdaf-2mutants growing on CBX102 was dependent on the FOXO orthologue DAF-16. Since the DAF-2/DAF-16 axis is present in most metazoans this suggests an evolutionary conserved host mechanism to modify a pathogen to a commensal.
Biallelic variants in the RNA exosome geneEXOSC5are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness
Authors: Slavotinek Anne , Misceo Doriana , Htun Stephanie , Mathisen Linda , Frengen Eirik , Foreman Michelle , Hurtig Jennifer E. , Enyenihi Liz , Sterrett Maria C. , Leung Sara W. , Schneidman-Duhovny Dina , Estrada-Veras Juvianee , Duncan Jacque L. , Xia Vivian , Beleford Daniah , Si Yue , Douglas Ganka , Treidene Hans Einar , van Hoof Ambro , Fasken Milo B. , Corbett Anita H.
Published: April 2020

The RNA exosome is an essential ribonuclease complex involved in the processing and degradation of both coding and noncoding RNAs. We present three patients with biallelic variants inEXOSC5, which encodes a structural subunit of the RNA exosome. The common clinical features of these patients comprise failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. The first patient had a deletion involving exons 5-6 ofEXOSC5and a missense variant, p.Thr114Ile, that were inheritedin trans, the second patient was homozygous for p.Leu206His, and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. We employed three complementary approaches to explore the requirement forEXOSC5in brain development and assess the functional consequences of pathogenic variants inEXOSC5. Loss of function for the zebrafish ortholog results in shortened and curved tails and bodies, reduced eye and head size and edema. We modeled pathogenicEXOSC5variants in both budding yeast and mammalian cells. Some of these variants show defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. Overall, these findings expand the number of genes encoding RNA exosome components that have been implicated in human disease, while also suggesting that disease mechanism varies depending on the specific pathogenic variant.
Genetic Developmental Timing Revealed by Inter-Species Transplantations in Fish
Authors: Fuhrmann Jana Franziska , Buono Lorena , Martinez Morales Juan Ramón , Centanin Lázaro
Published: April 2020

The path from a fertilised egg to an embryo involves the coordinated formation of cell types, tissues and organs. Developmental modules (Raff, 1996) comprise discrete units specified by self-sufficient genetic programs that can interact among each other during embryogenesis. Here we took advantage of the different span of embryonic development between two far related teleosts, zebrafish (Danio rerio) and medaka (Oryzias latipes), of 3 and 9 days respectively, to explore modularity principles. We report that inter-species blastula transplantations result in the ectopic formation of a retina formed by donor cells — a module. We show that the developmental time of the retina follows a genetic program: an ectopic zebrafish retina in medaka develops with zebrafish dynamics. Heterologous transplantation results in a temporal decoupling between the donor retina and host organism, illustrated by two paradigms that require retina-host interactions: lens recruitment and retino-tectal projections. Our results uncover a new experimental system to address temporal decoupling along embryonic development, and highlight the presence of largely autonomous but yet interconnected developmental modules orchestrating organogenesis.
Cell-type specialization in the brain is encoded by specific long-range chromatin topologies
Authors: Winick-Ng Warren , Kukalev Alexander , Harabula Izabela , Redondo Luna Zea , Szabo Dominik , Meijer Mandy , Serebreni Leonid , Zhang Yingnan , Bianco Simona , Chiariello Andrea M. , Irastorza-Azcarate Ibai , Fiorillo Luca , Musella Francesco , Thieme Christoph J. , Irani Ehsan , Triglia Elena Torlai , Kolodziejczyk Aleksandra A. , Abentung Andreas , Apostolova Galina , Paul Eleanor J. , Franke Vedran , Kempfer Rieke , Akalin Altuna , Teichmann Sarah A. , Dechant Georg , Ungless Mark A. , Nicodemi Mario , Welch Lonnie , Castelo-Branco Gonçalo , Pombo Ana
Published: April 2020

Neurons and oligodendrocytes are terminally differentiated cells that sustain cascades of gene activation and repression to execute highly specialized functions, while retaining homeostatic control. To study long-range chromatin folding without disturbing the native tissue environment, we developed Genome Architecture Mapping in combination with immunoselection (immunoGAM), and applied it to three cell types from the adult murine brain: dopaminergic neurons (DNs) from the midbrain, pyramidal glutamatergic neurons (PGNs) from the hippocampus, and oligodendroglia (OLGs) from the cortex. We find cell-type specific 3D chromatin structures that relate with patterns of gene expression at multiple genomic scales, including extensive reorganization of topological domains (TADs) and chromatin compartments. We discover the loss of TAD insulation, or ‘TAD melting’, at long genes (>400 kb) when they are highly transcribed. We find many neuron-specific contacts which contain accessible chromatin regions enriched for putative binding sites for multiple neuronal transcription factors, and which connect cell-type specific genes that are associated with neurodegenerative disorders such as Parkinson’s disease, or specialized functions such as synaptic plasticity and memory. Lastly, sensory receptor genes exhibit increased membership in heterochromatic compartments that establish strong contacts in brain cells. However, their silencing is compromised in a subpopulation of PGNs with molecular signatures of long-term potentiation. Overall, our work shows that the 3D organization of the genome is highly cell-type specific, and essential to better understand mechanisms of gene regulation in highly specialized tissues such as the brain.
Population dynamics with threshold effects give rise to a diverse family of Allee effects
Authors: Fadai Nabil T. , Simpson Matthew J.
Published: April 2020

The Allee effect describes populations that deviate from logistic growth models and arises in applications including ecology and cell biology. A common justification for incorporating Allee effects into population models is that the population in question has altered growth mechanisms at some critical density, often referred to as athreshold effect. Despite the ubiquitous nature of threshold effects arising in various biological applications, the explicit link between local threshold effects and global Allee effects has not been considered. In this work, we examine a continuum population model that incorporates threshold effects in the local growth mechanisms. We show that this model gives rise to a diverse family of Allee effects and we provide a comprehensive analysis of which choices of local growth mechanisms give rise to specific Allee effects. Calibrating this model to a recent set of experimental data describing the growth of a population of cancer cells provides an interpretation of the threshold population density and growth mechanisms associated with the population.
Targeted chemotherapy overcomes drug resistance in melanoma
Authors: Yue Jingyin , Vendramin Roberto , Liu Fan , Lopez Omar , Valencia Monica G. , Gomes Dos Santos Helena , Gaidosh Gabriel , Beckedorff Felipe , Blumenthal Ezra , Speroni Lucia , Nimer Stephen D. , Marine Jean-Christophe , Shiekhattar Ramin
Published: April 2020

The emergence of drug resistance is a major obstacle for the success of targeted therapy in melanoma. Additionally, conventional chemotherapy has not been effective as drug-resistant cells escape lethal DNA damage effects by inducing growth arrest commonly referred to as cellular dormancy. We present a therapeutic strategy termed “targeted chemotherapy” by depleting protein phosphatase 2A (PP2A) or its inhibition using a small molecule inhibitor (1,10-phenanthroline-5,6-dione [phendione]) in drug-resistant melanoma. Targeted chemotherapy induces the DNA damage response without causing DNA breaks or allowing cellular dormancy. Phendione treatment reduces tumor growth of BRAFV600E-driven melanoma patient-derived xenografts (PDX) and diminishes growth of NRASQ61R-driven melanoma, a cancer with no effective therapy. Remarkably, phendione treatment inhibits the acquisition of resistance to BRAF inhibition in BRAFV600E PDX highlighting its effectiveness in combating the advent of drug resistance.
Assessing the regional sustainability performance in China using the global Malmquist-Luenberger productivity index
Authors: Liu Kai-di , Yang Duo-Gui , Yang Guoliang , Zhou Zhi-Tian
Published: April 2020

Purpose

This paper aims to investigate the situation and evolution of sustainability performance in China.

Design/methodology/approach

This paper adopts the global Malmquist-Luenberger (GML) productivity index based on data envelopment analysis and Tobit regression for analysis.

Findings

The results indicate the following: China’s sustainability performance has been improving since 2005 and is closely related to the national development strategy and supportive policy; regional gaps in sustainability are a prominent problem represented by the fact that South Central China is becoming a sustainability collapse zone; interprovincial heterogeneity is evident with the varying development speed and conditions; and the level of sustainability performance has a significantly positive correlation with the urbanization rate, investment completed in the treatment of industrial pollution, government appropriation for education and per capita area of paved roads, but it has a negative correlation with the possession of private vehicles.

Originality/value

As an application, this study assessing the GML productivity index of 30 provinces in China from 2005 to 2015 and analyse the sustainability performance on three regional levels (i.e. country level, regional level and provincial level). Tobit regression is also applied to recognize the factors related to the GML index with the results taken as references for policy suggestions. The results have implications for a comprehensive understanding of China's sustainability performance and policymaking in this field.
Past behaviour, financial literacy and investment decision-making process of individual investors
Authors: Raut Rajdeep Kumar
Published: April 2020

Purpose

This study aims to explore the importance of past behaviour and financial literacy in the investment decision-making of individual investors and examines the validity of the theory of planned behaviour in this context.

Design/methodology/approach

The study used a self-administered questionnaire and adopted the convenience sampling technique followed by a snowball sampling method for the survey to collect data from the individual investors covering the four distinct states of India. Collected data were analysed on AMOS 20.0 using two-step structural equation modelling (SEM).

Findings

Results indicated a significant effect of all the predictive variables. Past behaviour showed no significant direct impact on investor's intention; however, it had an indirect significant relationship while mediated by the attitude of investors. The multiple squared correlation (R2) showed that the final model could explain 36% of the variance in investors' intention towards stock investment which signified a successful implementation of the TPB model along with external variables added to it. Moreover, Indian investors were found to be highly influenced, primarily, by social pressure which could be curbed through financial literacy.

Practical implications

A significant importance of subjective norms was found on stock market participation which could be a strategic theme for the government and the policymakers to educate investors through their opinion leaders for increasing their participation. Moreover, by doing so investors could control their behaviour and take rational decisions.

Originality/value

This study extended the understandings of investor's decision-making behaviour using TPB by incorporating the two external variables viz., Financial literacy and past behaviour. The addition of past behaviour is perhaps the novelty of this article since such examination has not been conducted empirically especially in the case of developing countries like India.
From knowing the game to enjoying the game: EEG/ERP assessment of emotional processing
Authors: Lee Hyun-Woo , Cho Heetae , Lasko Emily , Kim Jun Woo , Kwon Woong
Published: April 2020

Purpose

In highlighting brain wave responses of emotional processing, the purpose of this study is to investigate (1) the effect of sport participation involvement on affective reaction in viewing photos; and (2) the association between affective reaction and behavioral intentions.

Design/methodology/approach

Using lateralized event-related potentials, the authors examined how brain wave reactions are different based on different sport involvement between two groups where one group had varsity sport experience while the other expressed that they were not fans of the sport.

Findings

Results indicated a significant difference in lateralization between groups. Brain responses were greater in the high involvement group and positively correlated with the intention to attend future games.

Originality/value

The findings in this study elucidate the linkage between one's history of sport involvement and affective brain wave responses. Implications from neurophysiological evidence provide means to further dissect the multifaceted construct of involvement in the field of sport marketing.
Australian office workers' response to sedentary behaviour messaging
Authors: Chapman Janine , Fletcher Chloe , Corsini Nadia , de Cure Georgina
Published: April 2020

Purpose

To provide insight into how office workers respond to sedentary health messages following the introduction of the Australian Physical Activity and Sedentary Behaviour Guidelines.

Design/methodology/approach

Via online survey, office workers (n = 185) reported awareness of the Guidelines and sedentary risk, availability of workplace movement-based initiatives, and measures of sitting time, intention, self-efficacy, and perceived barriers to sedentary behaviour. Participants then viewed one of two brief messages (“Occupational Risk” or “Strategies”); indicated their message receptivity and provided written recommendations. Participants who consented to a second survey (n = 126) completed sitting time and psychological measures again after four weeks.

Findings

Only 23% were aware of the Guidelines; willingness to follow public health guidance was mixed. Barriers to adoption were apparent for existing initiatives. Message receptivity was high for both messages. For the follow-up survey, an improvement in psychological variables and workplace sitting was reported in those who viewed the Occupational Risk compared to the Strategies message. Qualitative analysis revealed lack of organisational support and called for increased employer responsibility.

Research limitations/implications

As participants self-selected into the study, the sample may be more health-conscious than the typical office worker.

Practical implications

Workers are receptive to brief messages and the Occupational Risk message showed promise in promoting change. However, sedentary exposure is viewed as an organisational-level issue. A “whole of workplace” approach is needed with co-designed strategies tailored to the culture and working practices within the organisation.

Originality/value

This study offers insight into avenues for improving the management of prolonged sitting and workplace sedentary behaviour.