bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dissecting thePyrenophora tritici-repentis(tan spot of wheat) pangenome
Authors: Gourlie Ryan , McDonald Megan , Hafez Mohamed , Ortega-Polo Rodrigo , Low Kristin E. , Abbott D. Wade , Strelkov Stephen E. , Daayf Fouad , Aboukhaddour Reem 
Published: March 2022

ABSTRACTWe sequenced the genome of a global collection (40 isolates) of the fungusPyrenophora tritici-repentis(Ptr), a major foliar pathogen of wheat and model for the evolution of necrotrophic pathogens. Ptr exhibited an open-pangenome, with 43% of genes in the core set and 57% defined as accessory (present in only a subset of isolates), of which 56% were singleton genes (present in only one isolate). A clear distinction between pathogenic and non-pathogenic genomes was observed in size, gene content, and phylogenetic relatedness. Chromosomal rearrangements and structural organization, specifically around the effector coding genes, were explored further using the annotated genomes of two isolates sequenced by PacBio RS II and Illumina HiSeq. The Ptr genome exhibited major chromosomal rearrangements, including chromosomal fusion, translocation, and segment duplications. An intraspecies translocation ofToxA, the necrosis-inducing effector-coding gene, was facilitated within Ptr via a 143 kb ‘Starship’transposon (dubbed ‘Horizon’). Additionally,ToxB, the gene encoding the chlorosis-inducing effector, was clustered as three copies on a 294 kb transposable element in a ToxB-producing isolate.ToxBand its carrying transposon were missing from theToxBnon-coding reference isolate, but the homologtoxband the transposon were both present in another non-coding isolate. The Ptr genome also appears to exhibit a ‘one-compartment’ organization, but may still possess a ‘two-speed genome’ that is facilitated by copy-number variation as reported in other fungal pathosystems.IMPORTANCEPtr is one of the most destructive wheat pathogens worldwide. Its genome is a mosaic of present and absent effectors, and serves as a model for examining the evolutionary processes behind the acquisition of virulence in necrotrophs and disease emergence. In this work, we took advantage of a diverse collection of pathogenic Ptr isolates with different global origins and applied short- and long-read sequencing technologies to dissect the Ptr genome. This study provides comprehensive insights into the Ptr genome and highlights its structural organization as an open pangenome with ‘one-compartment’. In addition, we identified the potential involvement of transposable elements in genome expansion and the movement of virulence factors. The ability of effector-coding genes to shuffle across chromosomes on large transposons was illustrated by the intraspecies translocation ofToxAand the multi-copyToxB. In terms of gene contents, the Ptr genome exhibits a large percentage of orphan genes, particularly in non-pathogenic or weakly-virulent isolates.
Differential correlation across subpopulations of single cells in subtypes of acute myeloid leukemia
Authors: McGee Reginald L. , Behbehani Gregory K. , Coombes Kevin R. 
Published: March 2022

AbstractMass cytometers can record 40-50 parameters per single cell for millions of cells in a sample, and in particular, for leukemic cells. Many methods have been developed to cluster phenotypically similar cells within cytometry data, but there are fewer methods to visualize activity and interactions of pairs of proteins across these populations. We have developed a workflow for analyzing correlations associated with predfined populations. By clustering blood samples from acute myeloid leukemia (AML) patients and normal controls using an established algorithm, we obtained a minimum spanning tree of clusters of single cells. Using surface marker expression, we identified clusters on the tree that belonged to phenotypes of interest. Next, we computed correlations between pairs of proteins in each cluster. We developed a novel, coherent, probability-based statistic to test differences between vectors of correlation coefficients. By comparing all combinations of the normal controls under the statistic, we created an empirical distribution that provided a conservative measure of differential correlation. Using this empirically-derived distribution to define significance, we compared pooled samples from AML subtypes and normal controls to detect differential correlations. Given the structure present within this cytometry data set, we found it natural to consider correlations in this manner versus aggregating all data and computing a single correlation. Our results have the advantage that we can localize the statistical measure to determine contributions from particular phenotypic populations. Differentially correlated pairs of proteins can be further explored by considering a population’s distribution of correlation coefficients or biaxially plotting protein expressions within individual cells in a given population. Our approach leads to a better understanding of the nonlinear relationships that exist in the cytometry data.Author summaryWe introduce a novel method for analyzing the abundance of single cell data collected by high-throughput technologies. Due to the high dimensionality of such datasets, there is a need for methods to identify significant interactions between genes or proteins. In particular, we are interested in statistical differences between correlations of proteins within populations of cells determined by traditional immunophenotyping techniques. In this paper, we have demonstrated the utility of this new framework in the case of blood samples from individuals with different subtypes of leukemia and compare to healthy controls. The motivation for this application is that differences between can illuminate potential drivers of the disease. We have illustrated an example of how intracellular events can be detected by our statistic. Finally, this method is flexible in that it can also be applied in a variety of contexts where there are vectors of correlation coefficients that need to be compared.
Derivation and external validation of clinical prediction rules identifying children at risk of linear growth faltering (stunting) presenting for diarrheal care
Authors: Ahmed Sharia M. , Brintz Ben J. , Pavlinac Patricia B , Shahrin Lubaba , Huq Sayeeda , Levine Adam C. , Nelson Eric J. , Platts-Mills James A , Kotloff Karen L , Leung Daniel T 
Published: March 2022

ABSTRACTBackgroundNearly 150 million children under-5 years of age were stunted in 2020. We aimed to develop a clinical prediction rule (CPR) to identify children likely to experience additional stunting following acute diarrhea, to enable targeted approaches to prevent this irreversible outcome.MethodologyWe used clinical and demographic data from the Global Enteric Multicenter Study (GEMS) study to build predictive models of linear growth faltering (decrease of ≥0.5 or ≥1.0 in height-for-age z-score [HAZ] at 60 day follow-up) in children ≤59 months presenting with moderate-to-severe diarrhea (MSD), and community controls, in Africa and Asia. We screened variables using random forests, and assessed predictive performance with random forest regression and logistic regression using 5-fold cross-validation. We used the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study to A) re-derive, and B) externally validate our GEMS-derived CPR.ResultsOf 7639 children in GEMS, 1744 (22.8%) experienced severe growth faltering (≥0.5 decrease in HAZ). In MAL-ED, we analyzed 5683 diarrhea episodes from 1322 children, of which 961(16.9%) episodes experienced severe growth faltering. Top predictors of growth faltering in GEMS were: age, HAZ at enrollment, respiratory rate, temperature, and number of people living in the household. The maximum AUC was 0.75 (95% CI: 0.75, 0.75) with 20 predictors, while 2 predictors yielded an AUC of 0.71 (95% CI: 0.71, 0.72). Results were similar in the MAL-ED re-derivation. A 2-variable CPR derived from children 0-23 months in GEMS had an AUC=0.63 (95% CI 0.62, 0.65), and AUC=0.68 (95% CI: 0.63, 0.74) when externally validated in MAL-ED.ConclusionsOur findings indicate that use of prediction rules could help identify children at risk of poor outcomes after an episode of diarrheal illness.
Altered Heterogeneity of Ageing Lung Endothelium is a Hallmark of Idiopathic Pulmonary Fibrosis
Authors: Faulkner Eamon C. , Moverley Adam A. , Hart Simon P. , Nikitenko Leonid L. 
Published: March 2022

AbstractBackgroundOlder age is the main risk factor for chronic lung diseases including idiopathic pulmonary fibrosis (IPF). Halting or reversing progression of IPF remains an unmet clinical need due to limited knowledge of underlying mechanisms. The lung circulatory system, composed of blood (pulmonary and bronchial) and lymphatic vessels networks, has been implicated in IPF pathophysiology in elderly people, based solely on reports of altered density and increased permeability of vessels.AimWe aimed to define heterogeneity and IPF-associated changes of lung endothelial cells (EC or endothelium) by comparing gene expression in tissues from elderly people - transplant donors and recipients with IPF.MethodsSingle-cell RNA sequencing (scRNAseq) datasets of “ageing lung” tissues were selected only from those publicly available sources that contain age-matching samples for both groups (49- 77 years old donors and IPF patients; nine pairs in total), integrated and compared. Findings were validated by immunohistochemistry using EC-specific markers.ResultsThe generation of integrated single-cell maps of ageing lung tissues revealed 17 subpopulations of endothelium (12 for blood and 5 for lymphatic vessels, including 9 novel), with distinct transcriptional profiles. In IPF lung, the heterogeneity of ageing lung endothelium was significantly altered - both in terms of cell numbers (linked to disease- related changes in tissue composition) and differentially expressed genes (associated with fibrosis, inflammation, differentiation and vasodilation) in individual pulmonary, bronchial and lymphatic EC subpopulations.ConclusionsThese findings reveal underappreciated extent of heterogeneity and IPF-associated changes of ageing lung endothelium. Our data suggest direct involvement of specific subpopulations of ageing lung endothelium in IPF pathophysiology, uncovering cellular and molecular targets which may have potential diagnostic, prognostic and therapeutic relevance. This study creates a conceptual framework for appreciating the disease-specific heterogeneity of ageing lung endothelium as a hallmark of IPF.
Risk Perceptions and Private Protective Behaviors: Evidence from COVID-19 Pandemic*
Authors: Bundorf M. Kate , DeMatteis Jill , Miller Grant , Polyakova Maria , Streeter Jialu L. , Wivagg Jonathan 
Published: March 2022

AbstractWe analyze data from a survey we administered during the COVID-19 pandemic to investigate the relationship between people’s subjective beliefs about risks and their private protective behaviors. On average, people substantially overestimate the absolute level of risk associated with economic activity, but have correct signals about their relative risk. Subjective risk beliefs are predictive of changes in economic activities independently of government policies. Government mandates restricting economic behavior, in turn, attenuate the relationship between subjective risk beliefs and protective behaviors.
Crops grown in mixtures show niche partitioning in spatial water uptake
Authors: Schmutz Anja , Schöb Christian 
Published: March 2022

AbstractMore diverse plant communities generally produce more biomass than monocultures. This benefit of plant diversity is supposed to stem from resource partitioning of species in mixtures. Different plant species might use the resources spatially, temporally, or chemically in different ways. Along the same lines, for agricultural production crop mixtures outperform monocultures. Differences in vertical root distributions of crop species in mixtures could explain such higher yield.Here we used the stable isotopes of water and a Bayesian model to investigate the spatial water uptake patterns of six different crops species and how these patterns differ depending on the crop diversity. In addition, we calculated niche overlaps of water uptake as an indicator for belowground spatial niche partitioning, compared them among the different diversity levels, and linked them to productivity.The spatial water uptake pattern differed among crop species. The effect of crop diversity had a minor effect on water uptake but varied strongly depending on the crop species. Niche overlap in spatial water uptake was highest in monocultures and decreased strongly in mixtures. Furthermore, productivity in mixtures was higher compared to monoculture. Additionally, we showed that increased competition intensity leads to stronger changes in water uptake patterns.Synthesis. We found evidence for niche partitioning of spatial water uptake, and therefore complementary spatial root distribution, and higher productivity in crop mixtures compared to monocultures. Consequently, a more efficient use of soil resources in intercropping systems might explain their yield benefits.
A panoramic perspective on human phosphosites
Authors: Ramasamy Pathmanaban , Vandermarliere Elien , vranken Wim , Martens Lennart 
Published: March 2022

AbstractProtein phosphorylation is the most common post-translational reversible modification of proteins and is key in the regulation of many cellular processes. Due to this importance, phosphorylation is extensively studied, resulting in the availability of a large amount of mass spectrometry based phospho-proteomics data. Here, we leverage the information in these large-scale phospho-proteomics datasets, as contained in Scop3P, to analyze and characterize proteome-wide protein phosphorylation sites (P-sites). First, we set out to differentiate correctly observed P-sites from false positive sites using five complementary site properties. We then describe the context of these P-sites in terms of protein structure, solvent accessibility, structural transitions and disorder, and biophysical properties. We also investigate the relative prevalence of disease-linked mutations on and around P-sites. Moreover, we also assess structural dynamics of P-sites in their phosphorylated and unphosphorylated state. Our study shows that the residues that gets phosphorylated are more flexible than their equivalent non-phosphorylated residues. Our structural and biophysical analyses of P-sites in solvent inaccessible (buried) regions of proteins show that these sites are primarily found in multi-site phospho-proteins, where highly dynamic structural transitions can occur upon binding with another protein. Finally, our analysis of the biophysical properties of P-site mutations shows that P-site mutations that occur in structurally rigid regions are more often involved in disease.
Coevolution of the Tlx homeobox gene with medusa development (Cnidaria: Medusozoa)
Authors: Travert Matthew , Boohar Reed , Sanders Steven M. , Nicotra Matthew L. , Leclère Lucas , Steele Robert E. , Cartwright Paulyn 
Published: March 2022

AbstractThe jellyfish, or medusa, is a life cycle stage characteristic of the cnidarian subphylum Medusozoa. By contrast, the other cnidarian subphyla Anthozoa and Endocnidozoa lack a medusa stage. Of the medusozoan classes, Hydrozoa is the most diverse in terms of species number and life cycle variation. A notable pattern in hydrozoan evolution is that the medusa stage has been lost or reduced several times independently. Although this loss of the jellyfish stage is thought to be due to heterochrony, the precise developmental mechanisms underlying this complex pattern of medusa evolution are unknown. We found that the presence of the homeobox gene Tlx in cnidarian genomes is correlated with those medusozoans that have a medusa stage as part of their life cycle. Although Tlx is conserved in Bilateria and Cnidaria, it is missing in the genomes of anthozoans, endocnidozoans, and those hydrozoans that have lost the medusa stage. Selection analyses of Tlx across medusozoans revealed that hydrozoans undergo relatively relaxed selection compared to the other medusozoan classes, which may in part explain the pattern of multiple medusa losses. Differential expression analyses on three distantly related medusozoan representatives indicate an upregulation of Tlx during medusa development. In addition, Tlx expression is spatially restricted to regions of active development in medusae of the hydrozoan Podocoryna carnea. Our results suggest that Tlx plays a key role in medusa development and that the loss of this gene is likely linked to the repeated loss of the medusa life cycle stage.
Antibiotic-induced recombination in bacteria requires the formation of double-strand breaks
Authors: Nath Arpita , Roizman Dan , Pachaimuthu Nivetha , Blázquez Jesús , Rolff Jens , Rodríguez-Rojas Alexandro 
Published: March 2022

AbstractRecombination is an essential process in bacterial drug resistance evolution. Fluoroquinolones, an important class of antibiotics, are known to stimulate recombination in Escherichia coli. On the other hand, when bacteria are exposed to sublethal concentrations of different antibiotic families, including strong inducers of the SOS system, which upregulates recombination pathways, there is no detectable change in the recombination rate. Here we explore why fluoroquinolones, but not any other tested antimicrobials, increase recombination rates. One feature that makes the fluoroquinolones different from other antibiotics is the generation of DNA double-strand breaks (DSBs). We tested whether other antimicrobials known for their ability to cause double-strand breaks, such as mitomycin C and bleomycin, are also affecting bacterial recombination rate. We found that both drugs indeed affected recombination rates in E. coli. Furthermore, there was a positive correlation between the number of DNA double-strand breaks and the recombination frequency. The manipulation of the level of DSBs directly impacted the recombination frequency. These results imply that recombination, at least in Gram-negative bacteria, is conservative, and even if multiple copies of a DNA sequence are available, the basal recombination rate is low. Our results highlight that homologous recombination is intended more for DNA damage repair than generating diversity, or at least that they occur at a very different scale. We also show that only antibiotics that cause DNA double-strand breaks can increase genetic diversity via recombination. The stimulation of recombination by DSBs-causing antimicrobials is an additional factor leading to the risk of antibiotic resistance evolution.
A protocol for a multi-site case control study to evaluate child and adolescent mental health service transformation in England using the i-THRIVE model
Authors: Moore A , Baron-Cohen Lindley , Simes E , Chen S , Fonagy  
Published: March 2022

AbstractThe National i-THRIVE Programme seeks to evaluate the impact of the NHS England-funded whole system transformation on child and adolescent mental health services (CAMHS). This article reports on the design for a model of implementation that has been applied in CAMHS across over 70 areas in England using the ‘THRIVE’ needs-based principles of care. The implementation protocol in which this model, ‘i-THRIVE’ (implementing-THRIVE), will be used to evaluate the effectiveness of the THRIVE intervention is reported, together with the evaluation protocol for the process of implementation. To evaluate the effectiveness of i-THRIVE to improve care for children and young people’s mental health, a case-control design will be conducted. N = 10 CAMHS sites that adopt the i-THRIVE model from the start of the NHS England-funded CAMHS transformation will be compared to N = 10 ‘comparator sites’ that choose to use different transformation approaches within the same timeframe. Sites will be matched on population size, urbanicity, funding, level of deprivation and expected prevalence of mental health care needs. To evaluate the process of implementation, a mixed-methods approach will be conducted to explore the moderating effects of context, fidelity, dose, pathway structure and reach on clinical and service level outcomes. This study addresses a unique opportunity to inform the ongoing national transformation of CAMHS with evidence about a popular new model for delivering children and young people’s mental health care, as well as a new implementation approach to support whole system transformation. If the outcomes reflect benefit from i-THRIVE, this study has the potential to guide significant improvements in CAMHS by providing a more integrated, needs-led service model that increases access and involvement of patients with services and in the care they receive.
Genomic landscape of the DHA1 family in the newly emerged pathogen Candida auris and mapping substrate repertoire of the prominent member CauMdr1
Authors: Khatoon Rosy , Sharma Suman , Vishwakarma Poonam , Saini Amandeep , Aggarwal Parth , Lynn Andrew M. , Prakash Amresh , Prasad Rajendra , Banerjee Atanu 
Published: March 2022

ABSTRACTThe last decade has witnessed the rise of extremely threatening healthcare-associated multidrug resistant non-albicans Candida (NAC) species, Candida auris. Thus, understanding the molecular basis of antifungal resistance has emerged as the single most important goal amongst the research community. Since besides target alterations, efflux mechanisms contribute maximally to antifungal resistance, it is imperative to investigate their contributions in this pathogen. Of note, within the Major Facilitator Superfamily (MFS) of efflux pumps, Drug/H+ antiporter family 1 (DHA1) has been established as a predominant contributor towards xenobiotic efflux. Our study provides a complete landscape of DHA1 transporters encoded in the genome of C. auris. This study identifies 14 DHA1 transporters encoded in the genome of the pathogen. We also construct deletion and heterologous overexpression strains for the most important DHA1 drug transporter, viz., CauMdr1 to map the spectrum of its substrates. While the knockout strain did not show any significant changes in the resistance patterns against the majority of the tested substrates, the ortholog when overexpressed in a minimal background S. cerevisiae strain, AD1-8u-, showed significant enhancement in the Minimum inhibitory concentrations (MICs) against a large panel of antifungal molecules. Altogether, the present study provides a comprehensive template for investigating the role of DHA1 members of C. auris in antifungal resistance mechanisms.
The chromatin associated Sin3B is a critical regulator of DNA damage repair through the engagement of the Non-Homologous End Joining
Authors: Morales-Valencia Jorge , Calderon Alexander , Saini Siddharth , David Gregory 
Published: March 2022

ABSTRACTTranscription and DNA damage repair act in a coordinated manner. The scaffolding protein Sin3B serves as a transcriptional corepressor of hundreds of cell-cycle-related genes. However, the role of Sin3B during the DNA damage response still remains unknown. Here, we show that Sin3B depletion delays the resolution of DNA double-strand breaks (DSBs) and sensitizes cells to diverse DNA-damaging agents, including cisplatin and doxorubicin. Furthermore, Sin3B is rapidly recruited to DNA damage sites and interacts with other DDR proteins. Mechanistically, Sin3B promotes non-homologous end joining DNA repair by directing the accumulation of MDC1 at DBSs. Altogether, our findings impute an unexpected function for the transcriptional co-repressor Sin3B as a gatekeeper of genomic integrity, and point to the inhibition of the Sin3B chromatin modifying complex as a novel therapeutic vulnerability in cancer cells.