bluuebunny/crossref_metadata_2025_split huggingface dataset:
Robust clustering and interpretation of scRNA-seq data using reference component analysis
Authors: Schmidt Florian , Ranjan Bobby , Lin Quy Xiao Xuan , Krishnan Vaidehi , Joanito Ignasius , Honardoost Mohammad Amin , Nawaz Zahid , Venkatesh Prasanna Nori , Tan Joanna , Rayan Nirmala Arul , Ong S.Tiong , Prabhakar Shyam 
Published: February 2021

MotivationThe transcriptomic diversity of the hundreds of cell types in the human body can be analysed in unprecedented detail using single cell (SC) technologies. Though clustering of cellular transcriptomes is the default technique for defining cell types and subtypes, single cell clustering can be strongly influenced by technical variation. In fact, the prevalent unsupervised clustering algorithms can cluster cells by technical, rather than biological, variation.ResultsCompared tode novo(unsupervised) clustering methods, we demonstrate using multiple benchmarks that supervised clustering, which uses reference transcriptomes as a guide, is robust to batch effects. To leverage the advantages of supervised clustering, we present RCA2, a new, scalable, and broadly applicable version of our RCA algorithm. RCA2 provides a user-friendly framework for supervised clustering and downstream analysis of large scRNA-seq data sets. RCA2 can be seamlessly incorporated into existing algorithmic pipelines. It incorporates various new reference panels for human and mouse, supports generation of custom panels and uses efficient graph-based clustering and sparse data structures to ensure scalability. We demonstrate the applicability of RCA2 on SC data from human bone marrow, healthy PBMCs and PBMCs from COVID-19 patients. Importantly, RCA2 facilitates cell-type-specific QC, which we show is essential for accurate clustering of SC data from heterogeneous tissues. In the era of cohort-scale SC analysis, supervised clustering methods such as RCA2 will facilitate unified analysis of diverse SC datasets.AvailabilityRCA2 is implemented in R and is available atgithub.com/prabhakarlab/RCAv2
Simons Collaborative Marine Atlas Project (Simons CMAP): an open-source portal to share, visualize and analyze ocean data
Authors: Ashkezari Mohammad D. , Hagen Norland R. , Denholtz Michael , Neang Andrew , Burns Tansy C. , Morales Rhonda L. , Lee Charlotte P. , Hill Christopher N. , Armbrust E. Virginia 
Published: February 2021

AbstractSimons Collaborative Marine Atlas Project (Simons CMAP) is an open-source data portal that interconnects large, complex, and diverse public data sets currently dispersed in different formats across different Oceanography discipline-specific databases. Simons CMAP is designed to streamline the retrieval of custom subsets of data, the generation of data visualizations, and the analyses of diverse data, thus expanding the power of these potentially underutilized data sets for cross-disciplinary studies of ocean processes. We describe a unified architecture that allows numerical model outputs, satellite products, and field observations to be readily shared, mined, and integrated regardless of data set size or resolution. A current focus of Simons CMAP is integration of physical, chemical, and biological data sets essential for characterizing the biogeography of key marine microbes across ocean basins and seasonal cycles. Using a practical example, we demonstrate how our unifying data harmonization plans significantly simplifies and allows for systematic data integration across all Simons CMAP data sets.
A test statistic to quantify treelikeness in phylogenetics
Authors: Cherryh Caitlin , Minh Bui Quang , Lanfear Rob 
Published: February 2021

AbstractMost phylogenetic analyses assume that the evolutionary history of an alignment (either that of a single locus, or of multiple concatenated loci) can be described by a single bifurcating tree, the so-called the treelikeness assumption. Treelikeness can be violated by biological events such as recombination, introgression, or incomplete lineage sorting, and by systematic errors in phylogenetic analyses. The incorrect assumption of treelikeness may then mislead phylogenetic inferences. To quantify and test for treelikeness in alignments, we develop a test statistic which we call the tree proportion. This statistic quantifies the proportion of the edge weights in a phylogenetic network that are represented in a bifurcating phylogenetic tree of the same alignment. We extend this statistic to a statistical test of treelikeness using a parametric bootstrap. We use extensive simulations to compare tree proportion to a range of related approaches. We show that tree proportion successfully identifies non-treelikeness in a wide range of simulation scenarios, and discuss its strengths and weaknesses compared to other approaches. The power of the tree-proportion test to reject non-treelike alignments can be lower than some other approaches, but these approaches tend to be limited in their scope and/or the ease with which they can be interpreted. Our recommendation is to test treelikeness of sequence alignments with both tree proportion and mosaic methods such as 3Seq. The scripts necessary to replicate this study are available athttps://github.com/caitlinch/treelikeness
High-throughput and dosage-controlled intracellular delivery of large cargos by an acoustic-electric micro-vortices platform
Authors: Aghaamoo Mohammad , Chen Yu-Hsi , Li Xuan , Garg Neha , Jiang Ruoyu , Lee Abraham P. 
Published: February 2021

ABSTRACTIntracellular delivery of cargos for cell engineering plays a pivotal role in transforming medicine and biomedical discoveries. Recent advances in microfluidics and nanotechnology have opened up new avenues for efficient, safe, and controllable intracellular delivery, as they improve precision down to the single-cell level. Based on this capability, several promising micro- and nanotechnology approaches outperform viral and conventional non-viral techniques in offering dosage-controlled delivery and/or intracellular delivery of large cargos. However, to achieve this level of precision and effectiveness, they are either low in throughput, limited to specific cell types (e.g., adherent vs. suspension cells), or complicated to operate with. To address these challenges, here we introduce a versatile and simple-to-use intracellular delivery microfluidic platform, termed Acoustic-Electric Shear Orbiting Poration (AESOP). Hundreds of acoustic microstreaming vortices form the production line of the AESOP platform, wherein hundreds of thousands of cells are trapped, permeabilized, and mixed with exogenous cargos. Using AESOP, we show intracellular delivery of a wide range of molecules (from <1 kDa to 2 MDa) with high efficiency, cell viability, and dosage-controlled capability into both suspension and adherent cells and demonstrate throughput at 1 million cells/min per single chip. In addition, we demonstrate AESOP for two gene editing applications that require delivery of large plasmids: i) eGFP plasmid (6.1 kbp) transfection, and ii) CRISPR-Cas9-mediated gene knockout using a 9.3 kbp plasmid DNA encoding Cas9 protein and sgRNA. Compared to alternative platforms, AESOP not only offers dosage-controlled intracellular delivery of large plasmids (>6kbp) with viabilities over 80% and comparable delivery efficiencies, but also is an order of magnitude higher in throughput, compatible with both adherent and suspension cell lines, and simple to operate.
Can Carbon Nanofibers Affect Anurofauna? Study Involving NeotropicalPhysalaemus cuvieri(Fitzinger, 1826) Tadpoles
Authors: Guimarães Abraão Tiago Batista , Estrela Fernanda Neves , de Lima Rodrigues Aline Sueli , Nóbrega Rafael Henrique , Charlie-Silva Ives , Malafaia Guilherme 
Published: February 2021

ABSTRACTAlthough carbon nanotubes’ (CNTs) toxicity in different experimental systems (in vivoandin vitro) is known, little is known about the toxic effects of carbon nanofibers (CNFs) on aquatic vertebrates. We herein investigated the potential impact of CNFs (1 and 10 mg/L) by usingPhysalaemus cuvieritadpoles as experimental model. CNFs were able to induce nutritional deficit in animals after 48-h exposure to them, and this finding was inferred by reductions observed in body concentrations of total soluble carbohydrates, total proteins, and triglycerides. The increased production of hydrogen peroxide, reactive oxygen species and thiobarbituric acid reactive substances in tadpoles exposed to CNFs has suggested REDOX homeostasis change into oxidative stress. This process was correlated to the largest number of apoptotic and necrotic cells in the blood of these animals. On the other hand, the increased superoxide dismutase and catalase activity has suggested that the antioxidant system of animals exposed to CNFs was not enough to maintain REDOX balance. In addition, CNFs induced increase in acetylcholinesterase and butyrylcholinesterase activity, as well as changes in the number of neuromats evaluated on body surface (which is indicative of the neurotoxic effect of nanomaterials on the assessed model system). To the best of our knowledge, this is the first report on the impact of CNFs on amphibians; therefore, it broadened our understanding about ecotoxicological risks associated with their dispersion in freshwater ecosystems and possible contribution to the decline in the populations of anurofauna species.
Chromosome segregation fidelity is controlled by small changes in phospho-occupancy at the kinetochore-microtubule interface
Authors: Kucharski Thomas J. , Hards Rufus , Godek Kristina M. , Gerber Scott A. , Compton Duane A. 
Published: February 2021

SummaryKinetochore protein phosphorylation promotes the correction of erroneous microtubule attachments to ensure faithful chromosome segregation during cell division. Determining how phosphorylation executes error correction requires an understanding of whether kinetochore substrates are completely (i.e. all-or-none) or only fractionally phosphorylated. Using quantitative mass spectrometry (MS), we measured phospho-occupancy on the conserved kinetochore protein Hec1 (NDC80) that directly binds microtubules. None of the positions measured exceeded ∼50% phospho-occupancy, and the cumulative phospho-occupancy changed by only ∼20% in response to changes in microtubule attachment status. The narrow dynamic range of phospho-occupancy is maintained by ongoing phosphatase activity. Further, both Cdk1-Cyclin B1 and Aurora kinases phosphorylate Hec1 to enhance error correction in response to different types of microtubule attachment errors. Thus, networks of kinases and phosphatases maintain low inherent phospho-occupancy to promote microtubule attachment to kinetochores while providing for high sensitivity of kinetochore-microtubule attachments to very small changes in phospho-occupancy to ensure high mitotic fidelity.
Polyelectrolyte chain at thermal equilibrium: A comparison between the density functional theory framework (DFT) and the molecular dynamic simulations (MD)
Authors: Edwards Mike J. 
Published: February 2021

ABSTRACTBy means of the density functional theory framework (DFT) as well as the molecular dynamic simulations (MD), a polyelectrolyte chain (PE) in the good solvent conditions at thermal equilibrium is studied. The strength of the electrostatic interactions is varied by the Bjerrum length of the solvent. It turns out that average extension of a PE scales with the degree of polymerization, very much similar to a neutral polymer chain in good solvent. Remarkably, the difference between a PE and a neutral chain appears to be solely in the correlations among monomers which are stored in the Virial coefficients. Interestingly, upon increasing the Bjerrum length of solvent, the chain shrinks. This outcome is confirmed by the DFT framework as well as the MD simulations.SIGNIFICANCEThe significance of this study is that it strongly criticizes the idea (already mentioned in T. Kreer,Soft Matter,12, 3479 (2016)) that the PEs behave similar to a neutral ideal chain. This study could be useful in our understanding of biopolymers.
Predictive coding across the left fronto-temporal hierarchy during language comprehension
Authors: Wang Lin , Schoot Lotte , Brothers Trevor , Alexander Edward , Warnke Lena , Kim Minjae , Khan Sheraz , Hämäläinen Matti , Kuperberg Gina R. 
Published: February 2021

AbstractWe used MEG and ERPs to track the time-course and localization of evoked activity produced byexpected,unexpected plausibleandimplausiblewords during incremental language comprehension. We interpret the full pattern of evoked responses and functional connectivity within a hierarchical predictive coding framework in which evoked activity reflects residual information (error) that is passed up and down the cortical hierarchy. Between 300-500ms, the three conditions produced progressively larger responses within left temporal cortex (lexico-semantic prediction error), whileimplausibleinputs produced a selectively enhanced response within left inferior frontal cortex (event-level prediction error). Between 600-1000ms,unexpected plausiblewords activated left inferior frontal and middle temporal cortices (feedback activity that induced top-down shifts of event-level and lexico-semantic representations), while highlyimplausibleinputs activated posterior fusiform and medial temporal cortices, supporting orthographic reanalysis and new learning. Therefore, predictive coding may provide a unifying theory that links language comprehension to other domains of cognition.
SARS-CoV-2 vaccination induces neutralizing antibodies against pandemic and pre-emergent SARS-related coronaviruses in monkeys
Authors: Saunders Kevin O. , Lee Esther , Parks Robert , Martinez David R. , Li Dapeng , Chen Haiyan , Edwards Robert J. , Gobeil Sophie , Barr Maggie , Mansouri Katayoun , Alam S. Munir , Sutherland Laura L. , Cai Fangping , Sanzone Aja M. , Berry Madison , Manne Kartik , Kapingidza Anyway B. , Azoitei Mihai , Tse Longping V. , Scobey Trevor D. , Spreng Rachel L. , Rountree R. Wes , DeMarco C. Todd , Denny Thomas N. , Woods Christopher W. , Petzold Elizabeth W. , Oguin Thomas H. , Sempowski Gregory D. , Gagne Matthew , Douek Daniel C. , Tomai Mark A. , Fox Christopher B. , Seder Robert , Wiehe Kevin , Weissman Drew , Pardi Norbert , Acharya Priyamvada , Andersen Hanne , Lewis Mark G. , Moore Ian N. , Montefiori David C. , Baric Ralph S. , Haynes Barton F. 
Published: February 2021

SUMMARYBetacoronaviruses (betaCoVs) caused the severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks, and now the SARS-CoV-2 pandemic. Vaccines that elicit protective immune responses against SARS-CoV-2 and betaCoVs circulating in animals have the potential to prevent future betaCoV pandemics. Here, we show that immunization of macaques with a multimeric SARS-CoV-2 receptor binding domain (RBD) nanoparticle adjuvanted with 3M-052-Alum elicited cross-neutralizing antibody responses against SARS-CoV-1, SARS-CoV-2, batCoVs and the UK B.1.1.7 SARS-CoV-2 mutant virus. Nanoparticle vaccination resulted in a SARS-CoV-2 reciprocal geometric mean neutralization titer of 47,216, and robust protection against SARS-CoV-2 in macaque upper and lower respiratory tracts. Importantly, nucleoside-modified mRNA encoding a stabilized transmembrane spike or monomeric RBD protein also induced SARS-CoV-1 and batCoV cross-neutralizing antibodies, albeit at lower titers. These results demonstrate current mRNA vaccines may provide some protection from future zoonotic betaCoV outbreaks, and provide a platform for further development of pan-betaCoV nanoparticle vaccines.
The frequency and topology of pseudoorthologs
Authors: Smith Megan L. , Hahn Matthew W. 
Published: February 2021

AbstractPhylogenetics has long relied on the use of orthologs, or genes related through speciation events, to infer species relationships. However, identifying orthologs is difficult because gene duplication can obscure relationships among genes. Researchers have been particularly concerned with the insidious effects of pseudoorthologs—duplicated genes that are mistaken for orthologs because they are present in a single copy in each sampled species. Because gene tree topologies of pseudoorthologs may differ from the species tree topology, they have often been invoked as the cause of counterintuitive results in phylogenetics. Despite these perceived problems, no previous work has calculated the probabilities of pseudoortholog topologies, or has been able to circumscribe the regions of parameter space in which pseudoorthologs are most likely to occur. Here, we introduce a model for calculating the probabilities and branch lengths of orthologs and pseudoorthologs, including concordant and discordant pseudoortholog topologies, on a rooted three-taxon species tree. We show that the probability of orthologs is high relative to the probability of pseudoorthologs across reasonable regions of parameter space. Furthermore, the probabilities of the two discordant topologies are equal and never exceed that of the concordant topology, generally being much lower. We describe the species tree topologies most prone to generating pseudoorthologs, finding that they are likely to present problems to phylogenetic inference irrespective of the presence of pseudoorthologs. Overall, our results suggest that pseudoorthologs are less of a problem for phylogenetics than currently believed, which should allow researchers to greatly increase the number of genes used in phylogenetic inference.Significance StatementPhylogenetics has long relied on the use of orthologs, or genes related through speciation events, to infer species relationships. However, filtering datasets to include only orthologs is both difficult and restrictive, drastically limiting the amount of data available for phylogenetic inference. Here, we introduce a model to study the probability and topologies of pseudoorthologs—duplicated genes that are mistaken for orthologs because they are present in a single copy in each sampled species. We show that pseudoorthologs are rare and that, even when they are present, they should not mislead phylogenetic inference. Our results suggest that strict filtering to remove pseudoorthologs unnecessarily limits the amount of data used in phylogenetic inference.
Discovery of a molecular glue that enhances UPRmtto restore proteostasisviaTRKA-GRB2-EVI1-CRLS1 axis
Authors: Qi Li-Feng-Rong , Qian Cheng , Liu Shuai , Peng Chao , Zhang Mu , Yang Peng , Wu Ping , Li Ping , Xu Xiaojun 
Published: February 2021

AbstractLowering proteotoxicity is a potentially powerful approach for the treatment of neurological disorders, such as Parkinson’s disease. The unfolded protein response (UPR) is a major mechanism that preserves the network maintaining cellular proteostasis. In the present study, we developed the screening strategy to discover compounds that significantly enhanced the activation of mitochondrial UPR (UPRmt) through increasing cardiolipin content. We identified that ginsenoside Rg3 (Rg3) increased cardiolipin depending on cardiolipin synthase 1 (CRLS1) in both worms and in human neural cells. Using LiP-SMap (limited proteolysis-mass spectrometry) strategy, we identified GRB2 (growth factor receptor bound protein 2) as a direct target of Rg3 in human neural cells. Rg3 enhances the binding between GRB2 and TRKA, that transduces signalsviaphosphrorylation of ERK. We provide bioinformatic and experimental evidence that EVI1, the critical oncogenic transcriptional regulator in leukemia, binds toCRLS1promoter region and stimulatedCRLS1expression and subsequently increased cardiolipin content in the presence of Rg3. In a Parkinson’s disease mouse model, Rg3 restores motor function by protecting nigral dopaminergic neurons dependent on Grb2. Our data recapitulate the TRKA-GRB2-EVI1-CRLS1 axis in maintaining proteostasis in Parkinson’s diseaseviaUPRmt.
Discovery of photosynthesis genes through whole-genome sequencing of acetate-requiring mutants ofChlamydomonas reinhardtii
Authors: Wakao Setsuko , Shih Patrick M. , Guan Katharine , Schackwitz Wendy , Ye Joshua , Shih Robert M. , Chovatia Mansi , Sharma Aditi , Martin Joel , Wei Chia-Lin , Niyogi Krishna K. 
Published: February 2021

AbstractLarge-scale mutant libraries have been indispensable for genetic studies, and the development of next-generation genome sequencing technologies has greatly advanced efforts to analyze mutants. In this work, we sequenced the genomes of 660Chlamydomonas reinhardtiiacetate-requiring mutants, part of a larger photosynthesis mutant collection previously generated by insertional mutagenesis with a linearized plasmid. We identified 554 insertion events from 509 mutants by mapping the plasmid insertion sites through paired-end sequences, in which one end aligned to the plasmid and the other to a chromosomal location. Nearly all (96%) of the events were associated with deletions, duplications, or more complex rearrangements of genomic DNA at the sites of plasmid insertion, and 1405 genes in total were affected. Functional annotations of these genes were enriched in those related to photosynthesis, signaling, and tetrapyrrole synthesis as would be expected from a library enriched for photosynthesis mutants. Systematic manual analysis of the disrupted genes for each mutant generated a list of 273 higher-confidence candidate photosynthesis genes, and we experimentally validated two genes that are essential for photoautotrophic growth,CrLPA3andCrPSBP4. The inventory of candidate genes includes 55 genes from a phylogenomically defined set of conserved genes in green algae and plants. Altogether, 68 candidate genes encode proteins with previously characterized functions in photosynthesis inChlamydomonas, land plants, and/or cyanobacteria, 15 genes encode proteins previously shown to have functions unrelated to photosynthesis, and 190 genes encode proteins without any functional annotation, signifying that our results connect a function related to photosynthesis to these previously unknown proteins. This mutant library, with genome sequences that reveal the molecular extent of the chromosomal lesions and resulting higher-confidence candidate genes, represents a rich resource for gene discovery and protein functional analysis in photosynthesis.
Testing hypotheses of marsupial brain size variation using phylogenetic multiple imputations and a Bayesian comparative framework
Authors: Todorov Orlin S. , Blomberg Simone P. , Goswami Anjali , Sears Karen , Drhlík Patrik , Peters James , Weisbecker Vera 
Published: February 2021

AbstractConsiderable controversy exists about which hypotheses and variables best explain mammalian brain size variation. We use a new, high-coverage dataset of marsupial brain and body sizes, and the first phylogenetically imputed full datasets of 16 predictor variables, to model the prevalent hypotheses explaining brain size evolution using phylogenetically corrected Bayesian generalised linear mixed-effects modelling. Despite this comprehensive analysis, litter size emerges as the only significant predictor. Marsupials differ from the more frequently studied placentals in displaying much lower diversity of reproductive traits, which are known to interact extensively with many behavioural and ecological predictors of brain size. Our results therefore suggest that studies of relative brain size evolution in placental mammals may require targeted co-analysis or adjustment of reproductive parameters like litter size, weaning age, or gestation length. This supports suggestions that significant associations between behavioural or ecological variables with relative brain size may be due to a confounding influence of the extensive reproductive diversity of placental mammals.