bluuebunny/crossref_metadata_2025_split huggingface dataset:
Joint Microbial and Metabolomic Network Estimation with the Censored Gaussian Graphical Model
Authors: Ma Jing 
Published: September 2020

AbstractJoint analysis of microbiome and metabolomic data represents an imperative objective as the field moves beyond basic microbiome association studies and turns towards mechanistic and translational investigations. We present a censored Gaussian graphical model framework, where the metabolomic data are treated as continuous and the microbiome data as censored at zero, to identify direct interactions (defined as conditional dependence relationships) between microbial species and metabolites. Simulated examples show that our method metaMint performs favorably compared to existing ones. metaMint also provides interpretable microbe-metabolite interactions when applied to a bacterial vaginosis data set. R implementation of metaMint is available on GitHub.
Computational pharmacogenomics screen identifies synergistic statin-compound combinations as anti-breast cancer therapies
Authors: van Leeuwen Jenna , Ba-Alawi Wail , Branchard Emily , Longo Joseph , Silvester Jennifer , Cescon David W. , Haibe-Kains Benjamin , Penn Linda Z. , Gendoo Deena M.A. 
Published: September 2020

AbstractStatins are a family of FDA-approved cholesterol-lowering drugs that inhibit the rate-limiting enzyme of the metabolic mevalonate pathway, which have been shown to have anti-cancer activity. As therapeutic efficacy is increased when drugs are used in combination, we sought to identify agents, like dipyridamole, that potentiate statin-induced tumor cell death. As an antiplatelet agent dipyridamole will not be suitable for all cancer patients. Thus, we developed an integrative pharmacogenomics pipeline to identify agents that were similar to dipyridamole at the level of drug structure, in vitro sensitivity and molecular perturbation. To enrich for compounds expected to target the mevalonate pathway, we took a pathway-centric approach towards computational selection, which we called mevalonate drug network fusion (MVA-DNF). We validated two of the top ranked compounds, nelfinavir and honokiol and demonstrated that, like dipyridamole, they synergize with fluvastatin to potentiate tumor cell death by blocking the restorative feedback loop. This is achieved by inhibiting activation of the key transcription factor that induces mevalonate pathway gene transcription, sterol regulatory element-binding protein 2 (SREBP2). Mechanistically, the synergistic response of fluvastatin+nelfinavir and fluvastatin+honokiol was associated with similar transcriptomic and proteomic pathways, indicating a similar mechanism of action between nelfinavir and honokiol when combined with fluvastatin. Further analysis identified the canonical epithelial-mesenchymal transition (EMT) gene, E-cadherin as a biomarker of these synergistic responses across a large panel of breast cancer cell lines. Thus, our computational pharmacogenomic approach can identify novel compounds that phenocopy a compound of interest in a pathway-specific manner.Significance StatementWe provide a rapid and cost-effective strategy to expand a class of drugs with a similar phenotype. Our parent compound, dipyridamole, potentiated statin-induced tumor cell death by blocking the statin-triggered restorative feedback response that dampens statins pro-apoptotic activity. To identify compounds with this activity we performed a pharmacogenomic analysis to distinguish agents similar to dipyridamole in terms of structure, cell sensitivity and molecular perturbations. As dipyridamole has many reported activities, we focused our molecular perturbation analysis on the pathway inhibited by statins, the metabolic mevalonate pathway. Our strategy was successful as we validated nelfinavir and honokiol as dipyridamole-like drugs at both the phenotypic and molecular levels. Our pathway-specific pharmacogenomics approach will have broad applicability.
Potential impact on coagulopathy of gene variants of coagulation related proteins that interact with SARS-CoV-2
Authors: Holcomb David , Alexaki Aikaterini , Hernandez Nancy , Laurie Kyle , Kames Jacob , Hamasaki-Katagiri Nobuko , Komar Anton A. , DiCuccio Michael , Kimchi-Sarfaty Chava 
Published: September 2020

AbstractThrombosis has been one of the complications of the Coronavirus disease of 2019 (COVID-19), often associated with poor prognosis. There is a well-recognized link between coagulation and inflammation, however, the extent of thrombotic events associated with COVID-19 warrants further investigation. Poly(A) Binding Protein Cytoplasmic 4 (PABPC4), Serine/Cysteine Proteinase Inhibitor Clade G Member 1 (SERPING1) and Vitamin K epOxide Reductase Complex subunit 1 (VKORC1), which are all proteins linked to coagulation, have been shown to interact with SARS proteins. We computationally examined the interaction of these with SARS-CoV-2 proteins and, in the case of VKORC1, we describe its binding to ORF7a in detail. We examined the occurrence of variants of each of these proteins across populations and interrogated their potential contribution to COVID-19 severity. Potential mechanisms by which some of these variants may contribute to disease are proposed. Some of these variants are prevalent in minority groups that are disproportionally affected by severe COVID-19. Therefore, we are proposing that further investigation around these variants may lead to better understanding of disease pathogenesis in minority groups and more informed therapeutic approaches.Author summaryIncreased blood clotting, especially in the lungs, is a common complication of COVID-19. Infectious diseases cause inflammation which in turn can contribute to increased blood clotting. However, the extent of clot formation that is seen in the lungs of COVID-19 patients suggests that there may be a more direct link. We identified three human proteins that are involved indirectly in the blood clotting cascade and have been shown to interact with proteins of SARS virus, which is closely related to the novel coronavirus. We examined computationally the interaction of these human proteins with the viral proteins. We looked for genetic variants of these proteins and examined how these variants are distributed across populations. We investigated whether variants of these genes could impact severity of COVID-19. Further investigation around these variants may provide clues for the pathogenesis of COVID-19 particularly in minority groups.
DatingAlphaproteobacteriaevolution with eukaryotic fossils
Authors: Wang Sishuo , Luo Haiwei 
Published: September 2020

AbstractElucidating the timescale of evolution of bacteria is key to testing hypotheses on their co-evolution with eukaryotic hosts, which, however, is largely limited by the scarcity of bacterial fossils. Here, we incorporate eukaryotic fossils to date the divergence times ofAlphaproteobacteria, based on the endosymbiosis theory that mitochondria evolved from an alphaproteobacterial lineage. We estimate thatAlphaproteobacteriaarose ~1900 million years (Ma) ago, followed by rapid divergence of their major clades. We show that the origin ofRickettsiales, an order of obligate intracellular bacteria whose hosts are mostly animals, predates the emergence of animals for ~700 Ma but coincides with that of eukaryotes. This, together with reconstruction of ancestral hosts, strongly suggests that earlyRickettsialeslineages had established previously underappreciated interactions with unicellular eukaryotes. Our mitochondria-based approach displays higher precision and robustness to uncertainties compared with the traditional strategy using cyanobacterial fossils, and suggests that previous applications using divergence times of the modern hosts of symbiotic bacteria to date the bacterial tree of life may need to be revisited.
Cell culture-based shark karyotyping as a resource for chromosome-scale genome analysis
Authors: Uno Yoshinobu , Nozu Ryo , Kiyatake Itsuki , Higashiguchi Nobuyuki , Sodeyama Shuji , Murakumo Kiyomi , Sato Keiichi , Kuraku Shigehiro 
Published: September 2020

AbstractKaryotyping is indispensable for validating genome assemblies whose sequence lengths can be scaled up to chromosome sizes using modern methods and is traditionally performed using cytogenetic techniques. Karyotype reports of chondrichthyans are scarce, mainly because of their unique osmoregulatory mechanism, which hinders cell culture. Here, we focused on carpet shark species and the culture conditions for fibroblasts and lymphocytes. Using this method, we performed high-fidelity characterization of their karyotypes, namely 2n = 102 for the whale shark (Rhincodon typus) and zebra shark (Stegostoma fasciatum), and 2n = 106 for the brownbanded bamboo shark (Chiloscyllium punctatum) and whitespotted bamboo shark (C. plagiosum). We identified heteromorphic XX/XY sex chromosomes for the two latter species and demonstrated the first-ever fluorescencein situhybridization of shark chromosomes prepared from cultured cells. Our technical solution is applicable to diverse chondrichthyan species and will deepen the understanding of early vertebrate evolution at the molecular level.
Rapid, high-yield production of full-length SARS-CoV-2 spike ectodomain by transient gene expression in CHO cells
Authors: Stuible Matthew , Gervais Christian , Lord-Dufour Simon , Perret Sylvie , L’Abbe Denis , Schrag Joseph , St-Laurent Gilles , Durocher Yves 
Published: September 2020

ABSTRACTRecombinant forms of the spike protein of SARS-CoV-2 and related viruses have proven difficult to produce with good yields in mammalian cells. Given the panoply of potential COVID-19 diagnostic tools and therapeutic candidates that require purified spike protein and its importance for ongoing SARS-CoV-2 research, we have explored new approaches for spike production and purification. Three transient gene expression methods based on PEI-mediated transfection of CHO or HEK293 cells in suspension culture in chemically-defined media were compared for rapid production of full-length SARS-CoV-2 ectodomain. A high-cell-density protocol using DXB11-derived CHOBRI/rcTAcells gave substantially better yields than the other methods. Different forms of the spike were expressed, including the wild-type SARS-CoV-2 sequence and a mutated/stabilized form (to favor expression of the full-length spike in prefusion conformation), with and without fusion to putative trimerization domains. An efficient two-step affinity purification method was also developed. Ultimately, we have been able to produce highly homogenous preparations of full-length spike, both monomeric and trimeric, with yields of 100-150 mg/L. The speed and productivity of this method support further development of CHO-based approaches for recombinant spike protein manufacturing.
Exploring genetic resistance to Infectious Salmon Anaemia Virus in Atlantic salmon by genome-wide association and RNA sequencing
Authors: Gervais O. , Barria A. , Papadopoulou A. , Gratacap R. , Hillestad B. , Tinch A.E. , Martin S.A.M. , Robledo D , Houston R.D. 
Published: September 2020

ABSTRACTInfectious Salmonid Anaemia Virus (ISAV) causes a notifiable disease that poses a large threat for Atlantic salmon breeders and producers worldwide. There is no fully effective treatment or vaccine, and therefore selective breeding to increase resistance to ISAV in commercial strains of Atlantic salmon is a promising avenue for disease prevention. Genomic selection and potentially genome editing can be applied to enhance host resistance, and these approaches benefit from improved knowledge of the genetic and functional basis of the target trait. The aim of this study was to characterise the genetic architecture of resistance to ISAV in a commercial Atlantic salmon population and study its underlying functional genomic basis using RNA Sequencing. A total of 2,833 Atlantic salmon parr belonging to 194 families were exposed to ISAV in a cohabitation challenge in which cumulative mortality reached 63% over 55 days. A total of 1,353 animals were genotyped using a 55K SNP array, and the estimate of heritability for the trait of binary survival was 0.33 (±0.04). A genome-wide association analysis confirmed that resistance to ISAV was a polygenic trait, albeit a genomic region in chromosome 13 was significantly associated with resistance and explained 3% of the genetic variance. RNA sequencing of the heart of 16 infected (7 and 14 days post infection) and 8 control fish highlighted 4,927 and 2,437 differentially expressed genes at 7 and 14 days post infection respectively. The complement and coagulation pathway was down-regulated, while several metabolic pathways were up-regulated in infected fish compared to controls. The interferon pathway was mildly activated at 7 days and showed no sign of up-regulation at 14 days post infection, implying a crosstalk between host and virus. Comparison of the transcriptomic response of fish with high and low breeding values for resistance (4 high resistance and 4 low resistance animals per time point) highlighted TRIM25 as being up-regulated in resistant fish, suggesting it may be a key antiviral gene involved in the functional genetic basis of resistance to ISAV.
Chromatin accessibility analysis uncovers regulatory element landscape in prostate cancer progression
Authors: Uusi-Mäkelä Joonas , Afyounian Ebrahim , Tabaro Francesco , Häkkinen Tomi , Lussana Alessandro , Shcherban Anastasia , Annala Matti , Nurminen Riikka , Kivinummi Kati , Tammela Teuvo L.J. , Urbanucci Alfonso , Latonen Leena , Kesseli Juha , Granberg Kirsi J. , Visakorpi Tapio , Nykter Matti 
Published: September 2020

AbstractAberrant oncogene functions and structural variation alter the chromatin structure in cancer cells. While gene regulation by chromatin states has been studied extensively, chromatin accessibility and its relevance in aberrant gene expression during prostate cancer progression is not well understood. Here, we report a genome-wide chromatin accessibility analysis of clinical tissue samples of benign prostatic hyperplasia (BPH), untreated primary prostate cancer (PC) and castration-resistant prostate cancer (CRPC) and integrative analysis with transcriptome, methylome, and proteome profiles of the same samples to uncover disease-relevant regulatory elements and their association to altered gene expression during prostate cancer progression. While promoter accessibility is consistent during disease initiation and progression, at distal sites chromatin accessibility is variable enabling transcription factors (TFs) binding patterns that are differently activated in different patients and disease stages. We identify consistent progression-related chromatin alterations during the progression to CRPC. By studying the TF binding patterns, we demonstrate the activation and suppression of androgen receptor-driven regulatory programs during PC progression and identify complementary TF regulatory modules characterized by e.g. MYC and glucocorticoid receptor. By correlation analysis we assign at least one putative regulatory region for 62% of genes and 85% of proteins differentially expressed during prostate cancer progression. Taken together, our analysis of the chromatin landscape in PC identifies putative regulatory elements for the majority of cancer-associated genes and characterizes their impact on the cancer phenotype.
Global drivers of eukaryotic plankton biogeography in the sunlit ocean
Authors: Guilhem Sommeria-Klein , Romain Watteaux , Daniele Iudicone , Chris Bowler , Hélène Morlon 
Published: September 2020

AbstractEukaryotic plankton are a core component of marine ecosystems with exceptional taxonomic and ecological diversity. Yet how their ecology interacts with the environment to drive global distribution patterns is poorly understood. Here, we useTaraOceans metabarcoding data covering all the major ocean basins combined with a probabilistic model of taxon co-occurrence to compare the biogeography of 70 major groups of eukaryotic plankton. We uncover two main axes of biogeographic variation. First, more diverse groups display stronger biogeographic structure. Second, large-bodied consumers are structured by oceanic basins, mostly via the main currents, while small-bodied phototrophs are structured by latitude, with a comparatively stronger influence of environmental conditions. Our study highlights striking differences in biogeographies across plankton groups and investigates their determinants at the global scale.One-sentence summaryEukaryotic plankton biogeography and its determinants at global scale reflect differences in ecology and body size.
Universal Spectrum Explorer: A standalone (web-)application for cross-resource spectrum comparison
Authors: Schmidt Tobias , Samaras Patroklos , Dorfer Viktoria , Panse Christian , Kockmann Tobias , Bichmann Leon , van Puyvelde Bart , Perez-Riverol Yasset , Deutsch Eric W. , Kuster Bernhard , Wilhelm Mathias 
Published: September 2020

AbstractHere we present the Universal Spectrum Explorer (USE), a web-based tool based on IPSA for cross-resource (peptide) spectrum visualization and comparison (https://www.proteomicsdb.org/use/). Mass spectra under investigation can either be provided manually by the user (table format), or automatically retrieved from online repositories supporting access to spectral data via the universal spectrum identifier (USI), or requested from other resources and services implementing a newly designed REST interface. As a proof of principle, we implemented such an interface in ProteomicsDB thereby allowing the retrieval of spectra acquired within the ProteomeTools project or real-time prediction of tandem mass spectra from the deep learning framework Prosit. Annotated mirror spectrum plots can be exported from the USE as editable scalable high quality vector graphics. The USE was designed and implemented with minimal external dependencies allowing local usage and integration into other websites (https://github.com/kusterlab/universal_spectrum_explorer).
The Benefits of Mycorrhizae are Frequency-Dependent: A Case Study With a Non-Mycorrhizal Mutant of Pisum Sativum
Authors: McNickle Gordon G. , Guinel Frédérique C. , Sniderhan Anastasia E. , Wallace Cory A. , McManus Allison S. , Fafard Melissa M. , Baltzer Jennifer L 
Published: September 2020

ABSTRACTMutualisms are remarkably common in the plant kingdom. The mycorrhizal association which involves plant roots and soil fungi is particularly common, and found among members of the majority of plant families. This association is a resource-resource mutualism, where plants trade carbon-based compounds for nutrients, such as phosphorus and nitrogen, mined by the fungi.Evolutionary models usually assume that a mutation grants a small number of individual plants the ability to associate with mycorrhizal fungi, and that this subsequently spreads through the population resulting in the evolution of mutualism. This frequency-dependent hypothesis has been difficult to test, because it is rare to have members of the same species that are capable and incapable of forming the mutualism.Here we describe the results of an experiment that took advantage of a mutant pea (Pisum sativum L. R25) that is incapable of forming mycorrhizal (or rhizobial) associations, and differs from the wildtype (P. sativum cv. Sparkle) by a single recessive Mendelian allele (Pssym8). We grew each genotype either alone or in every combination of pairwise mixed- or same-genotype. We also present an evolutionary matrix game, which we parameterize from the experimental 15N results, that allows us to estimate the costs and benefits of the mutualism.We find that there was no difference between R25 and WT when grown with a competitor of the same genotype, but when R25 and WT compete, WT has a significant fitness advantage. From the model, we estimate that the benefit in units of fitness (g pod mass) obtained from direct plant nitrogen uptake is 22.2 g, and mycorrhizae increase this by only 0.6 g. The costs of plant nitrogen uptake are 9.4 g, while the cost of trade with mycorrhizae is 0.1g.From the model and experiment, we conclude that this relatively small cost-benefit ratio of the mycorrhizal association is enough to drive the evolution of mutualism in frequency-dependent selection. However, without the mutant R25 genotype we would not have been able to draw this conclusion. This validation of frequency-dependent evolutionary models is important for continued theoretical development.
Antagonism between killer yeast strains as an experimental model for biological nucleation dynamics
Authors: Giometto Andrea , Nelson David R , Murray Andrew W 
Published: September 2020

AbstractAntagonistic interactions are widespread in the microbial world and affect microbial evolutionary dynamics. Natural microbial communities often display spatial structure, which affects biological interactions, but much of what we know about microbial warfare comes from laboratory studies of well-mixed communities. To overcome this limitation, we manipulated two killer strains of the budding yeastSaccharomyces cerevisiae,expressing different toxins, to independently control the rate at which they released their toxins. We developed mathematical models that predict the experimental dynamics of competition between toxin-producing strains in both well-mixed and spatially structured populations. In both situations, we experimentally verified theory’s prediction that a stronger antagonist can invade a weaker one only if the initial invading population exceeds a critical frequency or size. Finally, we found that toxin-resistant cells and weaker killers arose in spatially structured competitions between toxin-producing strains, suggesting that adaptive evolution can affect the outcome of microbial antagonism in spatial settings.
Open source 3D phenotyping of chickpea plant architecture across plant development
Authors: Salter William T. , Shrestha Arjina , Barbour Margaret M 
Published: September 2020

AbstractIn this work, we developed a low-cost 3D scanner and used an open source data processing pipeline to phenotype the 3D structure of individual chickpea plants. Being able to accurately assess the 3D architecture of plant canopies can allow us to better estimate plant productivity and improve our understanding of underlying plant processes. This is especially true if we can monitor these traits across plant development. Photogrammetry techniques, such as structure from motion, have been shown to provide accurate 3D reconstructions of monocot crop species such as wheat and rice, yet there has been little success reconstructing crop species with smaller leaves and more complex branching architectures, such as chickpea. The imaging system we developed consists of a user programmable turntable and three cameras that automatically captures 120 images of each plant and offloads these to a computer for processing. The capture process takes 5-10 minutes for each plant and the majority of the reconstruction process on a Windows PC is automated. Plant height and total plant surface area were validated against “ground truth” measurements, producing R2> 0.99 and a mean absolute percentage error < 10%. We demonstrate the ability to assess several important architectural traits, including canopy volume and projected area, and estimate relative growth rate in commercial chickpea cultivars and lines from local and international breeding collections. Detailed analysis of individual reconstructions also allowed us to investigate partitioning of plant surface area, and by proxy plant biomass.