bluuebunny/crossref_metadata_2025_split huggingface dataset:
Environmental DNA reveals the structure of phytoplankton assemblages along a 2900-km transect in the Mississippi River
Authors: Craine Joseph M. , Henson Michael W. , Thrash J. Cameron , Hanssen Jordan , Spooner Greg , Fleming Patrick , Pukonen Markus , Stahr Frederick , Spaulding Sarah , Fierer Noah 
Published: February 2018

AbstractThe environmental health of aquatic ecosystems is critical to society, yet traditional assessments of water quality have limited utility for some bodies of water such as large rivers. Sequencing of environmental DNA (eDNA) has the potential to complement if not replace traditional sampling of biotic assemblages for the purposes of reconstructing aquatic assemblages and, by proxy, assessing water quality. Despite this potential, there has been little testing of the ability of eDNA to reconstruct assemblages and their absolute and relative utility to infer water quality metrics. Here, we reconstruct phytoplankton communities by amplifying and sequencing DNA from a portion of the 23S rRNA region from filtered water samples along a 2900-km transect in the Mississippi River. Across the entire length, diatoms dominated the assemblage (72.6%) followed by cryptophytes (8.7%) and cyanobacteria (7.0%). There were no general trends in the abundances of these major taxa along the length of the river, but individual taxon abundance peaked in different regions. For example, the abundance of taxa genetically similar to Melosira tropica peaked at approximately 60% of all reads 2750 km upstream from the Gulf of Mexico, while taxa similar to Skeletonema marinoi began to increase below the confluence with the Missouri River until it reached approximately 30% of the reads at the Gulf of Mexico. There were four main clusters of samples based on phytoplankton abundance, two above the confluence with the Missouri and two below. Phytoplankton abundance was a poor predictor of NH4+ concentrations in the water, but predicted 61% and 80% of the variation in observed NO3-and PO43-concentrations, respectively. Phytoplankton richness increased with increasing distance along the river, but was best explained by phosphate concentrations and water clarity. Along the Mississippi transect, there was similar structure to phytoplankton and bacterial assemblages, indicating that the two sets of organisms are responding to similar environmental factors. In all, the research here demonstrates the potential utility of metabarcoding for reconstructing aquatic assemblages, which might aid in conducting water quality assessments.
Whole genome analysis illustrates global clonal population structure of the ubiquitous dermatophyte pathogenTrichophyton rubrum
Authors: Persinoti Gabriela F. , Martinez Diego A. , Li Wenjun , Döğen Aylin , Billmyre R. Blake , Averette Anna , Goldberg Jonathan M. , Shea Terrance , Young Sarah , Zeng Qiandong , Oliver Brian G. , Barton Richard , Metin Banu , Hilmioğlu-Polat Süleyha , Ilkit Macit , Gräser Yvonne , Martinez-Rossi Nilce M. , White Theodore C. , Heitman Joseph , Cuomo Christina A. 
Published: February 2018

AbstractDermatophytes include fungal species that infect humans, as well as those which also infect other animals or only grow in the environment. The dermatophyte speciesTrichophyton rubrumis a frequent cause of skin infection in immunocompetent individuals. While members of theT. rubrumspecies complex have been further categorized based on various morphologies, the population structure and ability to undergo sexual reproduction are not well understood. In this study, we analyze a large set ofT. rubrumandTrichophyton interdigitaleisolates to examine mating types, evidence of mating, and genetic variation. We find that nearly all isolates ofT. rubrumare of a single mating type, and that incubation withT. rubrummorphotypemegniniiisolates of the other mating type failed to induce sexual development. While the region around the mating type locus is characterized by a higher frequency of SNPs compared to other genomic regions, we find that the population is remarkably clonal, with highly conserved gene content, low levels of variation, and little evidence of recombination These results support a model of recent transition to asexual growth when this species specialized to growth on human hosts.Data access: Genome sequence data is available in NCBI under the Umbrella BioProject PRJNA186851.
Stronger connectivity of the resident gut microbiome lends resistance to invading bacteria
Authors: Herren Cristina M. , Baym Michael 
Published: February 2018

AbstractBacterial infection in the gut is often due to successful invasion of the host microbiome by an introduced pathogen. Ecological theory indicates that resident community members and their interactions should be strong determinants of whether an invading taxon can persist in a community. In the context of the gut microbiome, this suggests colonization resistance against newly introduced bacteria should depend on the instantaneous bacterial community composition within the gut and interactions between these constituent members. Here we develop a mathematical model of how metabolite-dependent biotic interactions between resident bacteria mediate invasion, and find that stronger biotic connectivity from metabolite cross-feeding and competition increases colonization resistance. We then introduce a statistical method for identifying invasive taxa in the human gut, and show empirically that greater connectivity of the resident gut microbiome is related to increased resistance to invading bacteria. Finally, we examined patient outcomes after fecal microbiota transplant (FMT) for recurring Clostridium difficile infection. Patients with lower connectivity of the gut microbiome after treatment were more likely to relapse, experiencing a later infection. Thus, simulation models and data from human subjects support the hypothesis that stronger interactions between bacteria in the gut repel invaders. These results demonstrate how ecological invasion theory can be applied to the gut microbiome, which might inform targeted microbiome manipulations and interventions. More broadly, this study provides evidence that low connectivity in gut microbial communities is a hallmark of community instability and susceptibility to invasion.
Removing Contaminants from Metagenomic Databases
Authors: Lu Jennifer , Salzberg Steven L. 
Published: February 2018

AbstractMetagenomic sequencing of patient samples is a very promising method for the diagnosis of human infections. Sequencing has the ability to capture all the DNA or RNA from pathogenic organisms in a human sample. However, complete and accurate characterization of the sequence, including identification of any pathogens, depends on the availability and quality of genomes for comparison. Thousands of genomes are now available, and as these numbers grow, the power of metagenomic sequencing for diagnosis should increase. However, recent studies have exposed the presence of contamination in published genomes, which when used for diagnosis increases the risk of falsely identifying the wrong pathogen.To address this problem, we have developed a bioinformatics system for eliminating contamination as well as low-complexity genomic sequences in the draft genomes of eukaryotic pathogens. We applied this software to identify and remove human, bacterial, archaeal, and viral sequences present in a comprehensive database of all sequenced eukaryotic pathogen genomes. We also removed low-complexity genomic sequences, another source of false positives. Using this pipeline, we have produced a database of “clean” eukaryotic pathogen genomes for use with bioinformatics classification and analysis tools. We demonstrate that when attempting to find eukaryotic pathogens in metagenomic samples, the new database provides better sensitivity than one using the original genomes while offering a dramatic reduction in false positives.
Transcriptome and metabolome analysis provide insights into root and root released organic anion responses to phosphorus deficiency in oat
Authors: Wang Yanliang , Lysøe Erik , Armarego-Marriott Tegan , Erban Alexander , Paruch Lisa , van Eerde Andre , Bock Ralph , Liu-Clarke Jihong 
Published: February 2018

AbstractRoot and root-released organic anions play important roles in uptake of phosphorus (P), an essential macronutrient for food production. Oat, ranking sixth in the world’s cereal production, contains valuable nutritional compounds and can withstand poor soil conditions. The aim of this research was to investigate root transcriptional and metabolic responses of oat grown under P-deficient and P-sufficient conditions. We conducted a hydroponic experiment and measured root morphology, organic anions exudation, and analysed changes in the transcriptome and metabolome, to understand oat root adaptation to P deficiency. We found that oat roots showed enhanced citrate and malate exudation after four weeks of P-deficiency. After 10 days of P-deficiency, we identified 9371 differentially expressed transcripts with a two-fold or greater change (p < 0.05): forty-eight sequences predicted to be involved in organic anion biosynthesis and efflux were consistently up-regulated; twenty-four up-regulated transcripts in oat were also found up-regulated upon P starvation in rice and wheat under similar conditions. Phosphorylated metabolites (i.e. glucose-6-phosphate, myo-inositol-phosphate) reduced dramatically, while citrate and malate, some sugars and amino acids increased slightly in P-deficient oat roots. Our data provide new insights into the root responses to P deficiency and root-released organic anions in oat.HighlightWe found oat- a monocot food crop, showed high exudation rate of citrate under phosphorus deficiency; root transcriptome and metabolome were then investigated to understand oat adaptation to P deficiency.
Genotypic and phenotypic diversity within the neonatal HSV-2 population
Authors: Akhtar Lisa N. , Bowen Christopher D. , Renner Daniel W. , Pandey Utsav , Della Fera Ashley N. , Kimberlin David W. , Prichard Mark N. , Whitley Richard J. , Weitzman Matthew D. , Szpara Moriah L. 
Published: February 2018

AbstractMore than 14,000 neonates are infected with herpes simplex virus (HSV) annually. Approximately half display manifestations limited to the skin, eyes, or mouth (SEM disease). The rest develop invasive infections that spread to the central nervous system (CNS disease or encephalitis) or systemically (disseminated disease). Invasive HSV disease is associated with significant morbidity and mortality, but viral and host factors that predispose neonates to these forms are unknown. To define viral diversity within the infected neonatal population, we evaluated ten HSV-2 isolates from newborns with a range of clinical presentations. To assess viral fitness independent of host immune factors, we measured viral growth characteristics in cultured cells and found diversein vitrophenotypes. Isolates from neonates with CNS disease were associated with larger plaque size and enhanced spread, with isolates from cerebrospinal fluid (CSF) exhibiting the most robust growth. We sequenced complete viral genomes of all ten neonatal viruses, providing new insights into HSV-2 genomic diversity in this clinical setting. We found extensive inter-host and intra-host genomic diversity throughout the viral genome, including amino acid differences in more than 90% of the viral proteome. The genes encoding glycoprotein G (gG, US4), gI (US7), gK (UL53), and viral proteins UL8, UL20, UL24, and US2 contained variants that were found in association with CNS isolates. Many of these viral proteins are known to contribute to cell spread and neurovirulence in mouse models of CNS disease. This study represents the first application of comparative pathogen genomics to neonatal HSV disease.ImportanceHerpes simplex virus (HSV) causes invasive disease in half of infected neonates, resulting in significant mortality and permanent cognitive morbidity. The factors that contribute to invasive disease are not understood. This study reveals diversity among HSV isolates from infected neonates, and makes the first associations between viral genetic variations and clinical disease manifestations. We found that viruses isolated from newborns with encephalitis show enhanced spread in culture. These viruses contain protein-coding variations not found in viruses causing non-invasive disease. Many of these variations are found in proteins known to impact neurovirulence and viral spread between cells. This work advances our understanding of HSV diversity in the neonatal population and how it may impact disease outcome.
Accelerated brain aging towards transcriptional inversion in a zebrafish model of familial Alzheimer’s disease
Authors: Hin Nhi , Newman Morgan , Kaslin Jan , Douek Alon M. , Lumsden Amanda , Zhou Xin-Fu , Ludington Alastair , Adelson David L. , Pederson Stephen , Lardelli Michael 
Published: February 2018

AbstractAlzheimer’s disease (AD) develops silently over decades. We cannot easily access and analyse pre-symptomatic brains, so the earliest molecular changes that initiate AD remain unclear. Previously, we demonstrated that the genes mutated in early-onset, dominantly-inherited familial forms of AD (fAD) are evolving particularly rapidly in mice and rats. Fortunately, some non-mammalian vertebrates such as the zebrafish preserve fAD-relevant transcript isoforms of the PRESENILIN (PSEN1 and PSEN2) genes that these rodents have lost. Zebrafish are powerful vertebrate genetic models for many human diseases, but no genetic model of fAD in zebrafish currently exists. We edited the zebrafish genome to model the unique, protein-truncating fAD mutation of human PSEN2, K115fs. Analysing the brain transcriptome and proteome of young (6-month-old) and aged, infertile (24-month-old) wild type and heterozygous fAD-like mutant female sibling zebrafish supports accelerated brain aging and increased glucocorticoid signalling in young fAD-like fish, leading to a transcriptional ‘inversion’ into glucocorticoid resistance and vast changes in biological pathways in aged, infertile fAD-like fish. Notably, one of these changes involving microglia-associated immune responses regulated by the ETS transcription factor family is preserved between our zebrafish fAD model and human early-onset AD. Importantly, these changes occur before obvious histopathology and likely in the absence of Aβ. Our results support the contributions of early metabolic and oxidative stresses to immune and stress responses favouring AD pathogenesis and highlight the value of our fAD-like zebrafish genetic model for elucidating early changes in the brain that promote AD pathogenesis. The success of our approach has important implications for future modelling of AD.
A role for tetracycline selection in the evolution of Clostridium difficile PCR-ribotype 078
Authors: Dingle Kate E. , Didelot Xavier , Quan T. Phuong , Eyre David W. , Stoesser Nicole , Marwick Charis A. , Coia John , Brown Derek , Buchanan Sarah , Ijaz Umer Z. , Goswami Cosmika , Douce Gill , Fawley Warren N. , Wilcox Mark H. , Peto Timothy E.A. , Walker A. Sarah , Crook Derrick W. 
Published: February 2018

ABSTRACTFarm animals have been identified as reservoirs of Clostridium difficile PCR-ribotype 078 (RT078). Since 2005, the incidence of human clinical cases (frequently severe), with this genotype has increased. We aimed to understand this change, by studying the recent evolutionary history of RT078. Phylogenetic analysis of international genomes (isolates from 2006–2014) revealed several recent clonal expansions. A common ancestor of each expansion had independently acquired different alleles of the tetracycline resistance gene tetM. Consequently, an unusually high proportion of RT078 genomes were tetM positive (76.5%). Additional tetracycline resistance determinants were also identified, some for the first time in C. difficile (efflux pump tet40). Each tetM-clonal expansion lacked geographic structure, indicating rapid international spread. Resistance determinants for C. difficile-infection-triggering antimicrobials including fluoroquinolones and clindamycin were comparatively rare in RT078. Tetracyclines are used intensively in agriculture; this selective pressure, plus rapid spread via the food-chain may explain the increased RT078 prevalence in humans.
Computational model of chimeric antigen receptors explains site-specific phosphorylation kinetics
Authors: Rohrs Jennifer A. , Zheng Dongqing , Graham Nicholas A. , Wang Pin , Finley Stacey D. 
Published: February 2018

AbstractChimeric antigen receptors (CARs) have recently been approved for the treatment of hematological malignancies, but our lack of understanding of the basic mechanisms that activate these proteins has made it difficult to optimize and control CAR-based therapies. In this study, we use phospho-proteomic mass spectrometry and mechanistic computational modeling to quantify thein vitrokinetics of individual tyrosine phosphorylation on a variety of CARs. We show that each of the ten tyrosine sites on the CD28-CD3ζ CAR is phosphorylated by LCK with distinct kinetics. The addition of CD28 at the N-terminal of CD3ζ increases the overall rate of CD3ζ phosphorylation. Our computational model identifies that LCK phosphorylates CD3ζ through a mechanism of competitive inhibition. This model agrees with previously published data in the literature and predicts that phosphatases in this system interact with CD3ζ through a similar mechanism of competitive inhibition. This quantitative modeling framework can be used to better understand CAR signaling and T cell activation.
A normalized drug response metric improves accuracy and consistency of anticancer drug sensitivity quantification in cell-based screening
Authors: Gupta Abhishekh , Gautam Prson , Wennerberg Krister , Aittokallio Tero 
Published: February 2018

ABSTRACTAccurate quantification of drug effects is crucial for identifying pharmaceutically actionable cancer vulnerabilities. Current cell viability-based measurements often lead to biased response estimates due to varying growth rates and experimental artifacts that explain part of the inconsistency in high-throughput screening results. We developed an improved drug scoring model, normalized drug response (NDR), which makes use of both positive and negative control conditions to account for differences in cell growth rates and experimental noise to better characterize drug-induced effects. We demonstrate an improved consistency and accuracy of NDR compared to existing metrics in assessing drug responses of cancer cells in various culture models and experimental setups. Notably, NDR reliably captures both toxicity and viability responses, and differentiates a wider spectrum of drug behavior, including lethal, growth-inhibitory and growth-stimulatory modes, based on a single viability readout. The method will therefore substantially reduce the time and resources required in cell-based drug sensitivity screening.
Neural Signatures of Reward and Sensory Prediction Error in Motor Learning
Authors: Palidis Dimitrios J. , Cashaback Joshua G.A. , Gribble Paul L. 
Published: February 2018

AbstractAt least two distinct processes have been identified by which motor commands are adapted according to movement-related feedback: reward based learning and sensory error based learning. In sensory error based learning, mappings between sensory targets and motor commands are recalibrated according to sensory error feedback. In reward based learning, motor commands are associated with subjective value, such that successful actions are reinforced. We designed two tasks to isolate reward and sensory error based motor adaptation, and recorded electroencephalography (EEG) from humans to identify and dissociate the neural correlates of reward and sensory error processing. We designed a visuomotor rotation task to isolate sensory error based learning which was induced by altered visual feedback of hand position. In a reward learning task, we isolated reward based learning induced by binary reward feedback that was decoupled from the visual target. We found that a fronto-central event related potential called the feedback related negativity (FRN) was elicited specifically by reward feedback but not sensory error feedback. A more posterior component called the P300 was evoked by feedback in both tasks. In the visuomotor rotation task, P300 amplitude was increased by sensory error induced by perturbed visual feedback, and was correlated with learning rate. In the reward learning task, P300 amplitude was increased by reward relative to non reward and by surprise regardless of feedback valence. We propose that during motor adaptation, the FRN might specifically mark reward prediction error while the P300 might reflect processing which is modulated more generally by prediction error.New and NoteworthyWe studied the event related potentials evoked by feedback stimuli during motor adaptation tasks that isolate reward and sensory error learning mechanisms. We found that the feedback related negativity was specifically elicited by reward feedback, while the P300 was observed in both tasks. These results reveal neural processes associated with different learning mechanisms and elucidate which classes of errors, from a computational standpoint, elicit the FRN and P300.
Complex evolutionary history of translation Elongation Factor 2 and diphthamide biosynthesis in Archaea and parabasalids
Authors: Narrowe Adrienne B. , Spang Anja , Stairs Courtney W. , Caceres Eva F. , Baker Brett J. , Miller Christopher S. , Ettema Thijs J. G. 
Published: February 2018

ABSTRACTDiphthamide is a modified histidine residue which is uniquely present in archaeal and eukaryotic elongation factor 2 (EF-2), an essential GTPase responsible for catalyzing the coordinated translocation of tRNA and mRNA through the ribosome. In part due to the role of diphthamide in maintaining translational fidelity, it was previously assumed that diphthamide biosynthesis genes (dph) are conserved across all eukaryotes and archaea. Here, comparative analysis of new and existing genomes reveals that some archaea (i.e., members of the Asgard superphylum,Geoarchaea, andKorarchaeota) and eukaryotes (i.e., parabasalids) lackdph. In addition, while EF-2 was thought to exist as a single copy in archaea, many of thesedph-lacking archaeal genomes encode a second EF-2 paralog missing key-residues required for diphthamide modification and for normal translocase function, perhaps suggesting functional divergence linked to loss of diphthamide biosynthesis. Interestingly, some Heimdallarchaeota previously suggested to be most closely related to the eukaryotic ancestor maintaindphgenes and a single gene encoding canonical EF-2. Our findings reveal that the ability to produce diphthamide, once thought to be a universal feature in archaea and eukaryotes, has been lost multiple times during evolution, and suggest that anticipated compensatory mechanisms evolved independently.