bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncovering complementary sets of variants for predicting quantitative phenotypes
Authors: Yılmaz Serhan , Fakhouri Mohamad , Koyutürk Mehmet , Çiçek A. Ercüment , Taştan Öznur 
Published: December 2020

AbstractMotivationGenome-wide association studies show that variants in individual genomic loci alone are not sufficient to explain the heritability of complex, quantitative phenotypes. Many computational methods have been developed to address this issue by considering subsets of loci that can collectively predict the phenotype. This problem can be considered a challenging instance of feature selection in which the number of dimensions (loci that are screened) is much larger than the number of samples. While currently available methods can achieve decent phenotype prediction performance, they either do not scale to large datasets or have parameters that require extensive tuning.ResultsWe propose a fast and simple algorithm, Macarons, to select a small, complementary subset of variants by avoiding redundant pairs that are in linkage disequilibrium. Our method features two interpretable parameters that control the time/performance trade-off without requiring parameter tuning. In our computational experiments, we show that Macarons consistently achieves similar or better prediction performance than state-of-the-art selection methods while having a simpler premise and being at least 2 orders of magnitude faster. Overall, Macarons can seamlessly scale to the human genome with ~107variants in a matter of minutes while taking the dependencies between the variants into account.ConclusionMacarons can offer a reasonable trade-off between phenotype predictivity, runtime and the complementarity of the selected subsets. The framework we present can be generalized to other high-dimensional feature selection problems within and beyond biomedical applications.AvailabilityMacarons is implemented in Matlab and the source code is available at:https://github.com/serhan-yilmaz/macarons
Pioneer activity of an oncogenic fusion transcription factor at inaccessible chromatin
Authors: Sunkel Benjamin , Wang Meng , LaHaye Stephanie , Kelly Benjamin J. , Fitch James R. , Barr Frederic G. , White Peter , Stanton Benjamin Z. 
Published: December 2020

SummaryRecent characterizations of pioneer transcription factors have led to new insights into their structures and patterns of chromatin recognition that are instructive for understanding their role in cell fate commitment and transformation. Intersecting with these basic science concepts, the identification of pioneer factors (PFs) fused together as driver translocations in childhood cancers raises questions of whether these fusions retain the fundamental ability to invade repressed chromatin, consistent with their monomeric PF constituents. In this study, we define the cellular and chromatin localization of the translocation, PAX3-FOXO1, an oncogenic driver of childhood rhabdomyosarcoma (RMS), derived from a genetic fusion of PFs. To quantitatively define its chromatin-targeting functions and capacity to drive epigenetic reprogramming, we developed a new method for ChIP-seq with per-cell normalization (pc-ChIP-seq). Our quantitative localization studies address structural variation in RMS genomes and reveal novel insights into heterochromatin localization of PAX3-FOXO1. From these studies, we report novel pioneer function for the major driver oncogene in RMS, with repressed chromatin binding and nucleosome-motif targeting in human cells.
Evaluation of established methods for DNA extraction and primer pairs targeting 16S rRNA gene for bacterial microbiome profiling of olive xylem sap
Authors: Haro Carmen , Anguita-Maeso Manuel , Metsis Madis , Navas-Cortés Juan A. , Landa Blanca B. 
Published: December 2020

AbstractNext Generation Sequencing has revolutionized our ability to investigate the microbiota composition of diverse and complex environments. However, a number of factors can affect the accuracy of microbial community assessment, such as the DNA extraction method, the hypervariable region of 16S rRNA gene targeted or the PCR primers used for amplification. The aim of this study was to assess the influence of commercially available DNA extraction kits and different primer pairs to provide a nonbiased vision of the composition of bacterial communities present in olive xylem sap. For that purpose, branches from ‘Picual’ and ‘Arbequina’ olive cultivars were used for xylem sap extraction using a Scholander chamber device. The DNA extraction protocol significantly affected xylem sap bacterial community assessment. That resulted in significant differences in alpha (Richness) and beta diversity (UNIFRAC distances) metrics among DNA extraction protocols, with the 12 DNA extraction kits evaluated being clustered in four groups behaving differently. Although the core number of taxa detected by all DNA extraction kits included four phyla, seven classes, 12 orders, and 16 or 21 families, and 12 or 14 genera when using the Greengenes or Silva database for taxonomic assignation, respectively, some taxa, particularly those identified at low frequency, were detected by some DNA extraction kits only. The most accurate depiction of a bacterial mock community artificially inoculated on sap samples was generated when using the PowerPlant DNA extraction Kit, the combination of 799F/1193R primers amplifying the hypervariable V5-V7 region and the Silva 132 database for taxonomic assignation. The DESeq2 analysis displayed significant differences among genera abundance between the different PCR primer pairs tested. Thus,Enterobacter, Granulicatella, PrevotellaandBrevibacteriumpresented a significant higher abundance in all PCR protocols when compared with primer pair 799F/1193R, while the opposite was true forPseudomonasandPectobacterium. The methodological approach followed in this study can be useful to optimize plant-associated microbiome analysis, especially when exploring new plant niches. Some of the DNA extraction kits and PCR primers selected in this study will contribute to better characterize bacterial communities inhabiting within the xylem sap of olives or other woody crop species.
Persistent Inward Currents Increase With The Level Of Voluntary Drive In Plantar Flexor Low-Threshold Motor Units
Authors: Orssatto Lucas B. R. , Mackay Karen , Shield Anthony J. , Sakugawa Raphael L. , Blazevich Anthony J. , Trajano Gabriel S. 
Published: December 2020

ABSTRACTThis study tested the hypothesis that estimates of persistent inward currents (PICs) in the human plantar flexors would increase with the level of voluntary drive. Twenty-one participants volunteered for this study (29.2±2.6 years). High-density surface electromyograms were collected fromsoleusandgastrocnemius medialisduring ramp-shaped isometric contractions to 10%, 20%, and 30% (torque rise of 2%/s and 30-s duration) of each participant’s maximal torque. Motor units identified in all the contraction intensities were included in the paired-motor unit analysis to calculate delta frequency (ΔF) and estimate the PICs. Increases in PICs were observed from 10% to 20% (Δ=0.6 pps; p<0.001) and 20% to 30% (Δ=0.5 pps; p<0.001) insoleus, and from 10% to 20% (Δ=1.2 pps; p<0.001) but not 20% to 30% (Δ=0.09 pps; p=0.724) ingastrocnemius medialis. Maximal discharge rate increased forsoleusandgastrocnemius medialisfrom 10% to 20% (respectively, Δ=1.75 pps, p<0.001; and Δ=2.43 pps, p<0.001) and 20% to 30% (respectively, Δ=0.80 pps, p<0.017; and Δ=0.92 pps, p=002). The repeated-measures correlation identified associations between ΔF and increases in maximal discharge rate for bothsoleus(r=0.64; p<0.001) andgastrocnemius medialis(r=0.77; p<0.001). An increase in voluntary drive tends to increase PIC strength, which has key implications for the control of force but also for comparisons between muscles or between studies when relative force levels might be different. These data indicate that increases in voluntary descending drive amplify PICs in humans and provide an important spinal mechanism for motor unit firing, and thus force output modulation.
Cross-species Transcriptomic Network Analysis Reveals Links Between Ribosomal Protein Mutation and Cancer
Authors: Denton Jai A , Velasque Mariana , Reed Floyd A 
Published: December 2020

AbstractRibosomal proteins (RPs) are critical to all cellular operations through their key roles in ribosome biogenesis and translation, as well as their extra-ribosomal functions. Leveraging previously identified RP mutants we characterised the RP macro transcriptome and sought to compare it with transcriptomes of pathologies associated with failures of ribosomal function, cancer and Zika virus (ZIKV). Single gene-based analysis revealed highly variable transcriptomes of RP mutations with little overlap in genes that were differentially expressed. In contrast, weighted gene co-expression network analysis revealed a highly conserved transcriptomic network pattern across all RP mutants studied. In addition, when we compared network changes in RP mutants, we observed similarities to transcriptome alterations in human cancer, and thus confirming the oncogenic role of RPs. Finally, it is known that ZIKV infection influences translational machinery, but this study shows infection network changes dissimilar to those of either the RP mutation or cancer.
Autonomous termination of proliferation in the Drosophila wing disc is TORC1 dependent
Authors: Strassburger Katrin , Lutz Marilena , Müller Sandra , Teleman Aurelio A. 
Published: December 2020

AbstractCells in a developing organ stop proliferating when the organ reaches a correct, final size. The underlying mechanisms are not understood. Although many signaling pathways and cell cycle components are required to sustain cell proliferation, which one of these turns off to terminate proliferation is not known. Here we study proliferation termination using Drosophila wing discs. We extend larval development to provide wing discs a constant growth-sustaining environment, allowing them to terminate proliferation autonomously. We find that the wing pouch, which forms the adult wing blade, terminates proliferation in the absence of brinker or warts, indicating that neither Dpp signaling nor Hippo/Yorkie signaling control final wing size. Instead, termination of proliferation coincides with reduced TORC1 activity and is bypassed by reactivating TORC1. Hence proliferation ceases due to reduced cell growth. Experimental manipulation of Dpp or Yki signaling can bypass proliferation termination in hinge and notum regions, suggesting that the mechanisms regulating proliferation termination may be distinct in different regions of the disc.One Sentence SummaryUsing Drosophila, Strassburger et al. investigate the termination of proliferation of an organ when it reaches its final size, and show this occurs due to a drop in TORC1 signaling.
Canonical TGFβ signaling induces collective invasion in colorectal carcinogenesis through a Snail1- and Zeb1-independent partial EMT
Authors: Flum Marion , Dicks Severin , Schrempp Monika , Nyström Alexander , Boerries Melanie , Hecht Andreas 
Published: December 2020

AbstractLocal invasion is the initial step towards metastasis, the main cause of cancer mortality. In human colorectal cancer (CRC), malignant cells predominantly invade as cohesive collectives, and may undergo partial epithelial-mesenchymal transition (pEMT) at the invasive front. How this particular mode of stromal infiltration is generated is unknown. Here we investigated the impact of oncogenic transformation and the microenvironment on tumor cell invasion using genetically engineered organoids as CRC models. We found that inactivation of the Apc tumor suppressor combined with expression of oncogenic KrasG12D and dominant negative Trp53R172H did not cell-autonomously induce invasion in vitro. However, oncogenic transformation primed organoids for activation of a collective invasion program upon exposure to the prototypical microenvironmental factor TGFβ1. Execution of this program co-depended on a permissive extracellular matrix which was further actively remodeled by invading organoids. Although organoids shed some epithelial properties particularly at the invasive edge, TGFβ1-stimulated organoids largely maintained epithelial gene expression while additionally implementing a mesenchymal transcription pattern, resulting in a pEMT phenotype that did not progress to a fully mesenchymal state. Induction of this stable pEMT required canonical, Smad4-mediated TGFβ signaling, whereas the EMT master regulators Snail1 and Zeb1 were dispensable. Gene expression profiling provided further evidence for pEMT of TGFβ1-treated organoids and showed that their transcriptomes resemble those of human poor prognosis CMS4 cancers which likewise exhibit pEMT features. We propose that collective invasion in colorectal carcinogenesis is triggered by microenvironmental stimuli through activation of a novel, transcription-mediated form of non-progressive pEMT independently of classical EMT regulators.
CellMixS: quantifying and visualizing batch effects in single cell RNA-seq data
Authors: Lütge Almut , Zyprych-Walczak Joanna , Kunzmann Urszula Brykczynska , Crowell HelenaL , Calini Daniela , Malhotra Dheeraj , Soneson Charlotte , Robinson Mark D 
Published: December 2020

AbstractA key challenge in single cell RNA-sequencing (scRNA-seq) data analysis are dataset- and batch-specific differences that can obscure the biological signal of interest. While there are various tools and methods to perform data integration and correct for batch effects, their performance can vary between datasets and according to the nature of the bias. Therefore, it is important to understand how batch effects manifest in order to adjust for them in a reliable way. Here, we systematically explore batch effects in a variety of scRNA-seq datasets according to magnitude, cell type specificity and complexity.We developed a cell-specific mixing score (cms) that quantifies how well cells from multiple batches are mixed. By considering distance distributions (in a lower dimensional space), the score is able to detect local batch bias and differentiate between unbalanced batches (i.e., when one cell type is more abundant in a batch) and systematic differences between cells of the same cell type. We implemented cms and related metrics to detect batch effects or measure structure preservation in the CellMixS R/Bioconductor package.We systematically compare different metrics that have been proposed to quantify batch effects or bias in scRNA-seq data using real datasets with known batch effects and synthetic data that mimic various real data scenarios. While these metrics target the same question and are used interchangeably, we find differences in inter- and intra-dataset scalability, sensitivity and in a metric’s ability to handle batch effects with differentially abundant cell types. We find that cell-specific metrics outperform cell type-specific and global metrics and recommend them for both method benchmarks and batch exploration.
Motor Imagery EEG neurofeedback skill acquisition in the context of declarative interference and sleep
Authors: Daeglau Mareike , Zich Catharina , Welzel Julius , Saak Samira Kristina , Scheffels Jannik Florian , Kranczioch Cornelia 
Published: December 2020

AbstractMotor imagery (MI) practice in combination with neurofeedback (NF) is a promising supplement to facilitate the acquisition of motor abilities and the recovery of impaired motor abilities following brain injuries. However, the ability to control MI NF is subject to a wide range of inter-individual variability. A substantial number of users experience difficulties in achieving good results, which compromises their chances to benefit from MI NF in a learning or rehabilitation context. It has been suggested that context factors, that is, factors outside the actual motor task, can explain individual differences in motor skill acquisition. Retrospective declarative interference and sleep have already been identified as critical factors for motor execution (ME) and MI based practice. Here, we investigate whether these findings generalize to MI NF practice.Three groups underwent three blocks of MI NF practice each on two subsequent days. In two of the groups, MI NF blocks were followed by either immediate or delayed declarative memory tasks. The control group performed only MI NF and no specific interference tasks. Two of the MI NF blocks were run on the first day of the experiment, the third in the morning of the second day. Significant within-block NF gains in mu and beta frequency event-related desynchronization (ERD) where evident for all groups. However, effects of sleep on MI NF ERD were not found. Data did also not indicate an impact of immediate or delayed declarative interference on MI NF ERD.Our results indicate that effects of sleep and declarative interference context on ME or MI practice cannot unconditionally be generalized to MI NF skill acquisition. The findings are discussed in the context of variable experimental task designs, inter-individual differences, and performance measures.
Quantum Approximated Graph Cutting: A Rapid Replacement for T-REMD?
Authors: Sandeep Samarth , Aramyan Sona , Poghosyan Armen H. , Gupta Vaibhav 
Published: December 2020

AbstractDetermining an optimal protein configuration for the employment of protein binding analysis as completed by Temperature based Replica Exchange Molecular Dynamics (T-REMD) is an important process in the accurate depiction of a protein’s behavior in different solvent environments, especially when determining a protein’s top binding sites for use in protein-ligand and protein-protein docking studies. However, the completion of this analysis, which pushes out top binding sites through configurational changes, is an polynomial-state computational problem that can take multiple hours to compute, even on the fastest supercomputers. In this study, we aim to determine if graph cutting provide approximated solutions the MaxCut problem can be used as a method to provide similar results to T-REMD in the determination of top binding sites of Surfactant Protein A (SP-A) for binding analysis. Additionally, we utilize a quantum-hybrid algorithm within Iff Technology’s Polar+ package using an actual quantum processor unit (QPU), an implementation of Polar+ using an emulated QPU, or Quantum Abstract Machine (QAM), on a large scale classical computing device, and an implementation of a classical MaxCut algorithm on a supercomputer in order to determine the types of advantages that can be gained through using a quantum computing device for this problem, or even using quantum algorithms on a classical device. This study found that Polar+ provides a dramatic speedup over a classical implementation of a MaxCut approximation algorithm or the use of GROMACS T-REMD, and produces viable results, in both its QPU and QAM implementations. However, the lack of direct configurational changes carried out onto the structure of SP-A after the use of graph cutting methods produces different final binding results than those produced by GROMACS T-REMD. Thus, further work needs to be completed into translating quantum-based probabilities into configurational changes based on a variety of noise conditions to better determine the accuracy advantage that quantum algorithms and quantum devices can provide in the near future.
Single cell transcriptomic analysis of bloodstream formTrypanosoma bruceireconstructs cell cycle progression and differentiation via quorum sensing
Authors: Briggs Emma M. , McCulloch Richard , Matthews Keith R. , Otto Thomas D. 
Published: December 2020

AbstractThe life cycles of African trypanosomes are dependent on several differentiation steps, where parasites transition between replicative and non-replicative forms specialised for infectivity and survival in mammal and tsetse fly hosts. Here, we use single cell transcriptomics (scRNA-seq) to dissect the asynchronous differentiation of replicative slender to transmissible stumpy bloodstream formTrypanosoma brucei. Using oligopeptide-induced differentiation, we accurately modelled stumpy developmentin vitroand captured the transcriptomes of 9,344 slender and stumpy stage parasites, as well as parasites transitioning between these extremes. Using this framework, we detail the relative order of biological events during development, profile dynamic gene expression patterns and identify putative novel regulators. Using marker genes to deduce the cell cycle phase of each parasite, we additionally map the cell cycle of proliferating parasites and position stumpy cell cycle exit at early G1, with subsequent progression to a distinct G0 state. We also explored the role of one gene, ZC3H20, with transient elevated expression at the key slender to stumpy transition point. By scRNA-seq analysis of ZC3H20 null parasites exposed to oligopeptides and mapping the resulting transcriptome to our atlas of differentiation, we identified the point of action for this key regulator. Using a developmental transition relevant for both virulence in the mammalian host and disease transmission, our data provide a paradigm for the temporal mapping of differentiation events and regulators in the trypanosome life cycle.
BNT162b vaccines are immunogenic and protect non-human primates against SARS-CoV-2
Authors: Vogel Annette B. , Kanevsky Isis , Che Ye , Swanson Kena A. , Muik Alexander , Vormehr Mathias , Kranz Lena M. , Walzer Kerstin C. , Hein Stephanie , Güler Alptekin , Loschko Jakob , Maddur Mohan S. , Ota-Setlik Ayuko , Tompkins Kristin , Cole Journey , Lui Bonny G. , Ziegenhals Thomas , Plaschke Arianne , Eisel David , Dany Sarah C. , Fesser Stephanie , Erbar Stephanie , Bates Ferdia , Schneider Diana , Jesionek Bernadette , Sänger Bianca , Wallisch Ann-Kathrin , Feuchter Yvonne , Junginger Hanna , Krumm Stefanie A. , Heinen André P. , Adams-Quack Petra , Schlereth Julia , Schille Stefan , Kröner Christoph , de la Caridad Güimil Garcia Ramón , Hiller Thomas , Fischer Leyla , Sellers Rani S. , Choudhary Shambhunath , Gonzalez Olga , Vascotto Fulvia , Gutman Matthew R. , Fontenot Jane A. , Hall-Ursone Shannan , Brasky Kathleen , Griffor Matthew C. , Han Seungil , Su Andreas A.H. , Lees Joshua A. , Nedoma Nicole L. , Mashalidis Ellene H. , Sahasrabudhe Parag V. , Tan Charles Y. , Pavliakova Danka , Singh Guy , Fontes-Garfias Camila , Pride Michael , Scully Ingrid L. , Ciolino Tara , Obregon Jennifer , Gazi Michal , Carrion Ricardo , Alfson Kendra J. , Kalina Warren V. , Kaushal Deepak , Shi Pei-Yong , Klamp Thorsten , Rosenbaum Corinna , Kuhn Andreas N. , Türeci Özlem , Dormitzer Philip R. , Jansen Kathrin U. , Sahin Ugur 
Published: December 2020

AbstractA safe and effective vaccine against COVID-19 is urgently needed in quantities sufficient to immunise large populations. We report the preclinical development of two BNT162b vaccine candidates, which contain lipid-nanoparticle (LNP) formulated nucleoside-modified mRNA encoding SARS-CoV-2 spike glycoprotein-derived immunogens. BNT162b1 encodes a soluble, secreted, trimerised receptor-binding domain (RBD-foldon). BNT162b2 encodes the full-length transmembrane spike glycoprotein, locked in its prefusion conformation (P2 S). The flexibly tethered RBDs of the RBD-foldon bind ACE2 with high avidity. Approximately 20% of the P 2S trimers are in the two-RBD ‘down,’ one-RBD ‘up’ state. In mice, one intramuscular dose of either candidate elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong TH1 CD4+and IFNγ+CD8+T-cell responses. Prime/boost vaccination of rhesus macaques with BNT162b candidates elicits SARS-CoV-2 neutralising geometric mean titres 8.2 to 18.2 times that of a SARS-CoV-2 convalescent human serum panel. The vaccine candidates protect macaques from SARS-CoV-2 challenge, with BNT162b2 protecting the lower respiratory tract from the presence of viral RNA and with no evidence of disease enhancement. Both candidates are being evaluated in phase 1 trials in Germany and the United States. BNT162b2 is being evaluated in an ongoing global, pivotal Phase 2/3 trial (NCT04380701,NCT04368728).