bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractThe 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

AbstractBackgroundThe 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.ConclusionsHere 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

AbstractBackgroundThe 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.ResultsHere 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.ConclusionOur 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

AbstractThe 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

AbstractWhilede 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

AbstractConjugation 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 StatementWe 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

ABSTRACTThermodynamic 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

SUMMARYIn 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

AbstractMigratory 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 SignificanceMigratory 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

ABSTRACTThe 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

AbstractThe 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

AbstractThe 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

AbstractNeurons 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.